4H-pyrido[1,2-a]pyrimidin-4-one compounds

ABSTRACT

The present invention relates to compounds of the formula I or II: (I) (II) processes for their preparation and their use as pharmaceutical agents or compositions in the treatment, of neurological disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is continuation of U.S. patent application Ser. No.16/409,296, filed May 10, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/529,891, filed May 25, 2017 and issued as U.S.Pat. No. 10,287,285 on May 14, 2019, which is a national stage entry ofInternational Application No. PCT/AU2015/000730, filed Dec. 2, 2015,which claims priority to Australian Patent Application No. 2014904868,filed Dec. 2, 2014, the disclosures of which are incorporated byreference in their entireties.

TECHNICAL FIELD

The present invention relates generally to pyrido[1,2-a]pyrimidin-4-onecompounds, processes for their preparation and their use aspharmaceutical agents or in compositions for the treatment ofneurological disorders.

BACKGROUND

Neurological disorders including neurodegenerative disorders can undergopathologically related reactions between proteins and the redox-activemetal ions, such as zinc, copper or iron. These reactions generatereactive oxygen species (ROS), which have the capacity to damagecellular components by oxidizing proteins, lipid bilayers, and DNA. Thiscan result in alterations of protein conformations, enzyme activitiesand cause protein aggregation.

ROS include free radicals such as superoxide anion, hydroxyl radical andother molecular species such as hydrogen peroxide (Bush and Goldstein(2001)). Hydroxyl radicals are the most reactive and damaging generatedROS. They are predominantly formed by a Fenton reaction betweentransition metals (usually iron(II) or copper(I)) and hydrogen peroxide.

Whilst cells possess antioxidant systems to protect against ROS damage,including protective enzymes such as copper-zinc superoxide dismutase,these enzymes contain metals. Cells must therefore maintain a carefulbalance between free and bound pro-oxidant versus antioxidant metalions, which are critical to cellular homeostasis. It is generallyconsidered that the aging brain has a slow and progressive imbalancebetween antioxidant defenses and intracellular concentrations of ROS.

There is a need to identify compounds designed to manage and modulateionic biological metals that, when unregulated, have an establishedassociation with a growing number of diseases including thosecharacterized by the presence of oxidative stress, protein aggregationand intracellular or extracellular metal imbalance.

SUMMARY

We have now found compounds which have two fused 6-membered rings withnitrogens at positions 1 and 5 and an OR⁸ group at position 9 which areuseful for treating neurological disorders. These compounds may possessone or more of the following properties: crosses the BBB, exhibitsreduced adverse side effects and/or are stable in aqueous environments.

In a first aspect, there is provided a compound of formula I

in which

R² is H, (CH₂)_(n)NR⁹R¹⁰, C₁₋₄ alkyl optionally interrupted with oxygenor (CH₂)_(n)SC═SNR⁹R¹⁰;

R³ is H, C₁₋₄ alkyl optionally interrupted with oxygen, C₁₋₄ alkoxy,C₃₋₆ cycloalkyl, (CH₂)_(m) optionally substituted aryl, (CH₂)_(n)optionally substituted aryl optionally fused with a 5 or 6 memberedheterocyclyl, C(O)NR⁹R¹⁰, (CH₂)_(n)NR⁹R¹⁰ or C(O)NH—N═CR⁹R¹⁰;

R⁵ is H or C₁₋₄ alkyl;

R⁶ is H, halo, (CH₂)_(n) optionally substituted 5 or 6 memberedheterocyclyl or C₂₋₄ alkynyl;

R⁷ is H, halo, (CH₂)_(n) 5 membered optionally substituted heterocyclyl,optionally substituted C₁₋₄ alkyl, C₂₋₄ alkynyl, (CH₂)_(n) NR⁹R¹⁰, NO₂,NR⁵SO₂ optionally substituted aryl or NR⁵SO₂ optionally substitutedC₁₋₄alkyl;

R⁸ is H, SO₂ optionally substituted aryl, C₁₋₄ alkyl or (CH₂)_(n) aryl;or

R⁷ together with the carbon atom to which it is attached and R⁸ togetherwith the oxygen atom to which it is attached from a 5 membered ring;

R⁹ and R¹⁰ are independently selected from H, C₁₋₈ alkyl optionallyinterrupted with O, CN, (CH₂)_(n) optionally substituted aryl optionallyfused with a 5 or 6 membered heterocyclyl, (CH₂)_(n) optionallysubstituted C₃₋₈ cycloalkyl, (CH₂)_(n) optionally substituted 5 or 6membered optionally substituted heterocyclyl, SO₂ optionally substitutedaryl and C₁₋₄ alkoxy; or

R⁹ and R¹⁰ together with the nitrogen atom to which they are attachedform a 5 or 6 membered optionally substituted heterocyclyl;

X is N or CH;

m is 1, 2 or 3; and

n is 0, 1, 2 or 3;

provided that:

-   -   (i) at least one of R², R³, R⁵, R⁶ and R⁷ is other than H;    -   (ii) when R³ is C₁₋₄ alkyl and R², R⁵ and Rare H, then R⁷ or R⁶        are other than H;    -   (iii) when R³ is C₁₋₄ alkyl, R², R⁵ and Rare H and R⁷ is I, then        R⁶ is other than H,

salts, isomers or prodrugs thereof or compounds selected from:

In a second aspect, there is provided a compound of formula II

in which

R², R³, R⁵, R⁶ and R⁷ are as defined in formula I above; and

M is transition metal;

salts, isomers or prodrugs thereof.

In a third aspect, there is provided a process for the preparation ofthe compound of formula I, salts, isomers or prodrugs thereof definedabove which comprises reacting a compound of formula III

in whichR⁵, R⁶, R⁷ and Rare as defined in formula I above;with a compound of formula IV

in whichR² and R³ are as defined in formula I above;to prepare a compound of formula V

in whichR², R³, R⁵, R⁶, R⁷ and Rare as defined in formula I above; andcyclisation of the compound of formula V.

In a fourth aspect, there is provided a process for the preparation ofthe compound of formula II, salts, isomers or prodrugs thereof definedabove which comprises reacting the compound of formula I, salts, isomersor prodrugs thereof defined above with a source of M in which M is asdefined in formula II above.

In a fifth aspect, there is provided a pharmaceutical agent comprisingthe compound of formula I or II, salts, isomers or prodrugs thereof asdefined above.

There is also provided a use of the compound of formula I or II, salts,isomers or prodrugs thereof as defined above as a pharmaceutical agent.

There is further provided the compound of formula I or II, salts,isomers or prodrugs thereof as defined above for use as a pharmaceuticalagent.

The pharmaceutical agent may be a neurotherapeutic or neuroprotectiveagent.

In a sixth aspect, there is provided neurotherapeutic or neuroprotectiveagent comprising the compound of formula I or II, salts, isomers orprodrugs thereof as defined above.

There is also provided use of the compound of formula I or II, salts,isomers or prodrugs thereof as defined above as a neurotherapeutic orneuroprotective agent.

There is further provided the compound of formula I or II, salts,isomers or prodrugs thereof as defined above for use as aneurotherapeutic or neuroprotective agent.

The compound of formula I or II, salts, isomers or prodrugs thereof maybe administered in the form of a pharmaceutical composition togetherwith a pharmaceutically acceptable carrier.

In a seventh aspect, there is provided a pharmaceutical compositioncomprising the compound of formula I or II, salts, isomers or prodrugsthereof and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical composition additionally comprisesa therapeutically effective amount of one or more further active agentssuch as a chemotherapeutic compound, immunotherapeutic compound,cytokine, genetic molecule and/or anesthetic.

In an eighth aspect, there is provided a method for the treatment of aneurological disorder which comprises administering an effective amountof the compound of formula I or II, salts, isomers or prodrugs thereofas defined above or the pharmaceutical agent or pharmaceuticalcomposition defined above to a subject in need thereof.

There is also provided use of the compound of formula I or II, salts,isomers or prodrugs thereof as defined above or the pharmaceutical agentor pharmaceutical composition as defined above in the manufacture of amedicament for the treatment of a neurological disorder.

There is further provided use of the compound of formula I or II, salts,isomers or prodrugs thereof as defined above or the pharmaceuticalcomposition as defined above for the treatment of a neurologicaldisorder.

There is still further provided the compound of formula I or II, salts,isomers or prodrugs thereof as defined above or the pharmaceutical agentor pharmaceutical composition defined above for use in the treatment ofa neurological disorder.

Although, the preferred subject is a human, the present invention hasapplication in the veterinary and animal husbandry industries and henceextends to non-human animals.

DETAILED DESCRIPTION

Compounds

The present invention relates to compounds of formula I defined above.

In one embodiment, the compound of formula I is a compound of formula Ia

in which R³ and R⁵ to R⁸ are as defined in formula I above.

In one embodiment of formula Ia, R³ is C₁₋₄ alkyl optionally interruptedwith O, C₅₋₆ cycloalkyl, (CH₂)_(n) optionally substituted aryloptionally fused with a 5 or 6 membered heterocyclyl, C(O)NR⁹ R¹⁰wherein R⁹ is H and R¹⁰ is C₁₋₆ alkyl, optionally substituted phenyl oroptionally substituted 5 membered heterocyclyl; R⁶ is H, halo such as Clor Br, 5 membered heterocyclyl optionally substituted with benzyl orcyclopentyl, C₁₋₄alkyl or C₂₋₄alkynyl; R⁷ is H, halo such as I, 5 or 6membered optionally substituted heterocyclyl, optionally substitutedphenyl, (CH₂)_(n)NR⁹ R¹⁰, C₁₋₄alkyl, C₂₋₄alkynyl or NR⁵SO₂ optionallysubstituted phenyl; and R⁸ is H or C₁₋₄alkyl.

Representative examples of compounds of formula Ia include compounds1235, 1607, 1621, 1622, 1623, 1624, 1643, 1599, 1611, 1650, 1674, 1675,1685, 1686, 1596, 1597, 1600, 1601, 1602, 1603, 1605, 1629, 1630, 1633,1639, 1641, 1648, 1651, 1652, 1653, 1654, 1655, 1656, 1659, 1660, 1668,1671, 1680, 1681, 1683, 1627, 1631, 1632, 1640, 1642, 1645, 1647, 1679,1691, 1693, 1706, 1606, 1615, 1616, 1617, 1626, 1613, 1619, 1620, 1625,1628, 1644, 1658, 1664, 1669, 1682, 1704, 1710, 1712, 1722, 1657, 1660,1661, 1717, 1708 and 1716 as shown in Schemes 1-4, 7-9 and 15-17 ofExamples 1-4, 7-9 and 15-17.

In another embodiment, the compound of formula I is a compound offormula Ib

in which R³ and R⁸ are as defined in formula I above

In one embodiment of formula Ib, R³ is H, C(O)NR⁹R¹⁰ or(C(O)N—NH═CR⁹R¹⁰; and R⁸ is H or benzyl.

Representative examples of compounds of formula Ib include 1394, 1422,1423, 1425, 1426, 1427, 1428, 1429, 1431, 1432, 1433, 1436, 1437, 1440,1441, 1445, 1446, 1447, 1450, 1452, 1453, 1454, 1461, 1462, 1532, 1533,1649, 1723, 1724 and 1732 as shown in Schemes 5 and 13 of Examples 5 and13.

In a further embodiment, the compound of formula I is a compound offormula Ic

in which R², R⁵, R⁶ and R⁸ are as defined in formula I above.

In one embodiment of formula Ic, R² is (CH₂)_(n)NR⁹R¹⁰, C₁₋₄alkyloptionally interrupted with O or (CH₂)_(n)SC═SNR⁹R¹⁰; R⁵ is H orC₁₋₄alkyl such as methyl; and R⁶ is halo such as Cl.

Representative examples of compounds of formula Ic include compounds1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411,1412, 1413, 1414, 1415, 1416, 1417, 1418, 1435, 1438, 1439, 1442, 1443,1444, 1448, 1449, 1451, 1455, 1456, 1457, 1458, 1459, 1463, 1464, 1466,1467, 1468, 1469, 1470, 1471, 1476, 1478, 1479, 1485, 1490, 1491, 1500,1503, 1504, 1506, 1508, 1515, 1516, 1517, 1518, 1519, 1521, 1522, 1523,1525, 1527, 1531, 1604, 1608, 1609, 1610, 1612, 1614, 1618, 1634, 1635,1636, 1637, 1638, 1670, 1699, 1707, 1591, 1646, 1701, 1705, 1713, 1714,1720 and 1721 as shown in Schemes 6, 10 and 12 of Examples 6, 10 and 12.

In a still further embodiment, the compound of formula I is a compoundof formula Id

in which R², R³ and R⁶ to R⁸ are as defined in formula I above.

In one embodiment of formula Id, R² is C₁₋₄alkyl such as methyl; R³ isC₁₋₄alkyl or benzyl; R⁶ is halo such as Cl; R⁷ is halo such as I or 5 or6 membered optionally substituted heterocyclyl; and R⁸ is H or C₁₋₄alkylsuch as propyl.

Representative examples of compounds of formula Id include compounds1662, 1663, 1665, 1666, 1667, 1672, 1673, 1687, 1688, 1689, 1690, 1694and 1698 as shown in Scheme 14 of Example 14.

In one embodiment, the compound of formula II is a compound of formulaIla.

in whichR³, R⁷ and M are as defined in formula II above.

In one embodiment of formula IIa, R³ is C₁₋₄alkyl such as propyl orC(O)NR⁹R¹⁰; R⁷ is C₁₋₄alkyl such as propyl and M is Zn or Cu.

Representative examples of compounds of formula Ia include compounds1678, 1692, 1700, 1715, 1718, 1719, 1744, 1745 and 1748 as shown inScheme 18 of Example 18.

Definitions

Unless otherwise herein defined, the following terms will be understoodto have the general meanings which follow.

The term “C₁₋₆alkyl” refers to optionally substituted straight chain orbranched chain hydrocarbon groups having from 1 to 6 carbon atoms.Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr),butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu),pentyl, neopentyl, hexyl and the like. Unless the context requiresotherwise, the term “C₁₋₆alkyl” also encompasses alkyl groups containingone less hydrogen atom such that the group is attached via two positionsi.e. divalent. “C₁₋₄alkyl” and “C₁₋₃alkyl” including methyl, ethyl,propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl arepreferred with methyl being particularly preferred.

The term “C₂₋₆alkenyl” refers to optionally substituted straight chainor branched chain hydrocarbon groups having at least one double bond ofeither E or Z stereochemistry where applicable and 2 to 6 carbon atoms.Examples include vinyl, 1-propenyl, 1- and 2-butenyl and2-methyl-2-propenyl. Unless the context requires otherwise, the term“C₂₋₆alkenyl” also encompasses alkenyl groups containing one lesshydrogen atom such that the group is attached via two positions i.e.divalent. “C₂₋₄alkenyl” and “C₂₋₃alkenyl” including ethenyl, propenyland butenyl are preferred with ethenyl being particularly preferred.

The term “C₂₋₆alkynyl” refers to optionally substituted straight chainor branched chain hydrocarbon groups having at least one triple bond and2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1- and2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl and the like. Unless thecontext indicates otherwise, the term “C₂₋₆alkynyl” also encompassesalkynyl groups containing one less hydrogen atom such that the group isattached via two positions i.e. divalent. C₂₋₄alkynyl is preferred.

The term “C₃₋₈cycloalkyl” refers to non-aromatic cyclic groups havingfrom 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. It will beunderstood that cycloalkyl groups may be saturated such as cyclohexyl orunsaturated such as cyclohexenyl. C₃₋₆cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl are preferred.

The terms “hydroxy” and “hydroxyl” refer to the group —OH.

The term “C₁₋₆alkoxy” refers to an alkyl group as defined abovecovalently bound via an O linkage containing 1 to 6 carbon atoms, suchas methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy and pentoxy.“C₁₋₄alkoxy” and “C₁₋₃alkoxy” including methoxy, ethoxy, propoxy andbutoxy are preferred with methoxy being particularly preferred.

The term “aryl” refers to a carbocyclic (non-heterocyclic) aromatic ringor mono-, bi- or tri-cyclic ring system. The aromatic ring or ringsystem is generally composed of 6 to carbon atoms. Examples of arylgroups include but are not limited to phenyl, biphenyl, naphthyl andtetrahydronaphthyl. 6-membered aryls such as phenyl are preferred. Theterm “alkylaryl” refers to C₁₋₆alkylaryl such as benzyl.

The term “heterocyclyl” refers to a moiety obtained by removing ahydrogen atom from a ring atom of a heterocyclic compound which moietyhas from 3 to 10 ring atoms (unless otherwise specified), of which 1, 2,3 or 4 are ring heteroatoms each heteroatom being independently selectedfrom O, S and N.

In this context, the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10-membereddenote the number of ring atoms, or range of ring atoms, whether carbonatoms or heteroatoms. For example, the term “3-10 memberedheterocyclyl”, as used herein, pertains to a heterocyclyl group having3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples of heterocyclyl groupsinclude 5-6-membered monocyclic heterocyclyls and 9-10 membered fusedbicyclic heterocyclyls.

Examples of monocyclic heterocyclyl groups include, but are not limitedto, those containing one nitrogen atom such as aziridine (3-memberedring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole),pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5-membered rings),piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), andazepine (7-membered ring); those containing two nitrogen atoms such asimidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline(dihydropyrazole) (5-membered rings), piperazine (6-membered ring);those containing one oxygen atom such as oxirane (3-membered ring),oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole(dihydrofuran) (5-membered rings), oxane (tetrahydropyran),dihydropyran, pyran (6-membered rings), oxepin (7-membered ring); thosecontaining two oxygen atoms such as dioxolane (5-membered ring), dioxane(6-membered ring), and dioxepane (7-membered ring); those containingthree oxygen atoms such as trioxane (6-membered ring); those containingone sulfur atom such as thiirane (3-membered ring), thietane (4-memberedring), thiolane (tetrahydrothiophene) (5-membered ring), thiane(tetrahydrothiopyran) (6-membered ring), thiepane (7-membered ring);those containing one nitrogen and one oxygen atom such astetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole(5-membered rings), morpholine, tetrahydrooxazine, dihydrooxazine,oxazine (6-membered rings); those containing one nitrogen and one sulfuratom such as thiazoline, thiazolidine (5-membered rings), thiomorpholine(6-membered ring); those containing two nitrogen and one oxygen atomsuch as oxadiazine (6-membered ring); those containing one oxygen andone sulfur such as: oxathiole (5-membered ring) and oxathiane (thioxane)(6-membered ring); and those containing one nitrogen, one oxygen and onesulfur atom such as oxathiazine (6-membered ring).

Heterocyclyls also encompass aromatic heterocyclyls and non-aromaticheterocyclyls. Such groups may be substituted or unsubstituted.

The term “aromatic heterocyclyl” may be used interchangeably with theterm “heteroaromatic” or the term “heteroaryl” or “hetaryl”. Theheteroatoms in the aromatic heterocyclyl group may be independentlyselected from N, S and O.

“Heteroaryl” is used herein to denote a heterocyclic group havingaromatic character and embraces aromatic monocyclic ring systems andpolycyclic (e.g. bicyclic) ring systems containing one or more aromaticrings. The term aromatic heterocyclyl also encompasses pseudoaromaticheterocyclyls. The term “pseudoaromatic” refers to a ring system whichis not strictly aromatic, but which is stabilized by means ofdelocalization of electrons and behaves in a similar manner to aromaticrings. The term aromatic heterocyclyl therefore covers polycyclic ringsystems in which all of the fused rings are aromatic as well as ringsystems where one or more rings are non-aromatic, provided that at leastone ring is aromatic. In polycyclic systems containing both aromatic andnon-aromatic rings fused together, the group may be attached to anothermoiety by the aromatic ring or by a non-aromatic ring.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to ten ring members. The heteroaryl group can be,for example, a five membered or six membered monocyclic ring or abicyclic structure formed from fused five and six membered rings or twofused six membered rings or two fused five membered rings. Each ring maycontain up to about four heteroatoms typically selected from nitrogen,sulphur and oxygen. The heteroaryl ring will contain up to 4heteroatoms, more typically up to 3 heteroatoms, more usually up to 2,for example a single heteroatom. In one embodiment, the heteroaryl ringcontains at least one ring nitrogen atom. The nitrogen atoms in theheteroaryl rings can be basic, as in the case of an imidazole orpyridine, or essentially non-basic as in the case of an indole orpyrrole nitrogen. In general the number of basic nitrogen atoms presentin the heteroaryl group, including any amino group substituents of thering, will be less than five.

Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclicaromatic ring systems.

Examples of 5-membered monocyclic heteroaryl groups include but are notlimited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e. 1,2,5-oxadiazolyl),thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl(including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl,thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like.

Examples of 6-membered monocyclic heteroaryl groups include but are notlimited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like.Examples of 6-membered aromatic heterocyclyls containing nitrogeninclude pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2nitrogens).

Aromatic heterocyclyl groups may also be bicyclic or polycyclicheteroaromatic ring systems such as fused ring systems (includingpurine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl,thieno[2,3-b]furyl and the like) or linked ring systems (such asoligothiophene, polypyrrole and the like). Fused ring systems may alsoinclude aromatic 5-membered or 6-membered heterocyclyls fused tocarbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl,fluorenyl, anthracenyl and the like, such as 5-membered aromaticheterocyclyls containing nitrogen fused to phenyl rings, 5-memberedaromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.

A bicyclic heteroaryl group may be, for example, a group selected from:a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ringcontaining 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrolering fused to a 5- or 6-membered ring containing 1, 2 or 3 ringheteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ringcontaining 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5-or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazolering fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ringcontaining 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or6-membered ring containing 1 or 2 ring heteroatoms; j) an isothiazolering fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms; k) a thiophene ring fused to a 5- or 6-membered ringcontaining 1, 2 or 3 ring heteroatoms; I) a furan ring fused to a 5- or6-membered ring containing 1, 2 or 3 ring heteroatoms; m) a cyclohexylring fused to a 5- or 6-membered ring containing 1, 2 or 3 ringheteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ringcontaining 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are notlimited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) andimidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuran, benzothiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole,isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline,purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.pyrazolo[1,5-a]pyrimidine), benzodioxole and pyrazolopyridine (e.g.pyrazolo[1,5-a]pyridine) groups. A further example of a six memberedring fused to a five membered ring is a pyrrolopyridine group such as apyrrolo[2,3-b]pyridine group.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman,benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine,quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine andpteridine groups.

Examples of heteroaryl groups containing an aromatic ring and anon-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline,tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran,2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.

Examples of aromatic heterocyclyls fused to carbocyclic aromatic ringsmay therefore include but are not limited to benzothiophenyl, indolyl,isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl,benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl,benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.

The term “non-aromatic heterocyclyl” encompasses optionally substitutedsaturated and unsaturated rings which contain at least one heteroatomselected from the group consisting of N, S and O.

Non-aromatic heterocyclyls may be 3-7 membered mono-cyclic rings.

Examples of 5-membered non-aromatic heterocyclyl rings include2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl,pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl,3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and thelike.

Examples of 6-membered non-aromatic heterocyclyls include piperidinyl,piperidinonyl, pyranyl, dihydropyranyl, tetrahydropyranyl, 2H pyranyl,4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl,diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-triozalanyl,1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl,triazinyl, 1,4-thiazinyl and the like.

Examples of 7-membered non-aromatic heterocyclyls include azepanyl,oxepanyl, thiepanyl and the like.

Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl ringssuch as linked ring systems (for example uridinyl and the like) or fusedring systems. Fused ring systems include non-aromatic 5-membered,6-membered or 7-membered heterocyclyls fused to carbocyclic aromaticrings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyland the like. Examples of non-aromatic 5-membered, 6-membered or7-membered heterocyclyls fused to carbocyclic aromatic rings includeindolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and thelike.

The term “halo” refers to fluoro, chloro, bromo or iodo.

The term “optionally substituted” refers to a group that may or may notbe further substituted with one or more groups selected from C_(1-g)alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heterocyclyl,halo, haloC₁₋₆alkyl, CF₃, haloC₃₋₆cycloalkyl, haloC₂₋₆alkenyl,haloC₂₋₆alkynyl, haloaryl, haloheterocycylyl, hydroxy, C₁₋₆ alkoxy,OCF₃, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, aryloxy, heterocyclyloxy, carboxy,haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy, haloC₂₋₆alkynyloxy, haloaryloxy,nitro, nitroC₁₋₆alkyl, nitroC₂₋₆alkenyl, nitroaryl, nitroheterocyclyl,azido, amino, C₁₋₆alkylamino, C₂₋₆alkenylamino, C₂₋₆alkynylamino,arylamino, heterocyclylamino acyl, C₁₋₆alkylacyl, C₂₋₆alkenylacyl,C₂₋₆alkynylacyl, arylacyl, heterocyclylacyl, acylamino, acyloxy,aldehydo, C₁₋₆alkylsulphonyl, arylsulphonyl, C₁₋₆alkylsulphonylamino,arylsulphonylamino, C₁₋₆alkylsulphonyloxy, arylsulphonyloxy, C₁₋₆alkylsulphenyl, C₂₋₆alklysulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, C₁₋₆alkylthio, arylthio, acylthio, cyano and thelike. Preferably, the optional substituent is C₁₋₄ alkyl, CF₃, hydroxy,halo such as Cl or F, C₁₋₄ alkoxy such as methoxy or OCF₃.

It will be understood that suitable derivatives of aromaticheterocyclyls containing nitrogen include N-oxides thereof.

The salts of the compounds of formula I or II are preferablypharmaceutically acceptable, but it will be appreciated thatnon-pharmaceutically acceptable salts also fall within the scope of thepresent invention, since these are useful as intermediates in thepreparation of pharmaceutically acceptable salts. Examples ofpharmaceutically acceptable salts include salts of pharmaceuticallyacceptable cations such as sodium, potassium, lithium, calcium,magnesium, ammonium and alkylammonium; acid addition salts ofpharmaceutically acceptable inorganic acids such as hydrochloric,orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric,sulfamic and hydrobromic acids; or salts of pharmaceutically acceptableorganic acids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic,succinic, oxalic, phenylacetic, methanesulphonic,trihalomethanesulphonic, toluenesulphonic, benzenesulphonic, salicylic,sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic,lauric, pantothenic, tannic, ascorbic and valeric acids. Salts of aminegroups may also comprise quaternary ammonium salts in which the aminonitrogen atom carries a suitable organic group such as an alkyl,alkenyl, alkynyl or aralkyl moiety.

The salts may be formed by conventional means, such as by reacting thefree base form of the compound with one or more equivalents of theappropriate acid.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, alcohols such as methanol, ethanol orisopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF) and thelike with the solvate forming part of the crystal lattice by eithernon-covalent binding or by occupying a hole in the crystal lattice.Hydrates are formed when the solvent is water, alcoholates are formedwhen the solvent is alcohol. Solvates of the compounds of the presentinvention can be conveniently prepared or formed during the processesdescribed herein. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Additionally, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds of the present invention are also considered to be disclosedherein.

It will be understood that compounds of formula I or II may possess achiral centre and may therefore exist as an isomer such as a racemate oran R- or S-enantiomer. The compounds may therefore be used as a purifiedenantiomer or diastereomer, or as a mixture of any ratio thereof. Theisomers may be separated conventionally by chromatographic methods orusing a resolving agent. Alternatively the individual isomers may beprepared by asymmetric synthesis using chiral intermediates. Where thecompound has a carbon-carbon double bond, it may occur in Z- or E-formand all isomeric forms of the compounds being included in the presentinvention.

This invention also encompasses prodrugs of the compounds of formula Ior II.

A prodrug may be a pharmacologically inactive derivative of the activecompound that requires transformation within the body in order torelease the active compound, and that has improved delivery propertiesover the active compound. The transformation in vivo may be, forexample, as the result of some metabolic process, such as chemical orenzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, orreduction or oxidation of a susceptible functionality. In oneembodiment, the OR⁸ group on the compounds of formula (I) may be blockedto form a prodrug when R⁸ is H, in particular an ester prodrug. Thehydroxy group represents a principal site of metabolism for thecompounds: conjugation with glucose glucuronic acid or sulphate gives ahydrophilic species ready to be excreted.

Included within the scope of this invention are compounds of the formulaI or II to which at least one of a detectable label, an affinity tag anda photoreactive group is linked.

Methods of Treatment

The compounds of formula (I) may be used in the treatment of aneurological disorder.

Generally, the term “treatment” means affecting a subject, tissue orcell to obtain a desired pharmacological and/or physiological effect andincludes: (a) inhibiting the neurological disorder, i.e. arresting itsdevelopment or further development; (b) relieving or ameliorating theeffects of the neurological disorder, i.e. cause regression of theeffects of the neurological disorder; (c) reducing the incidence or theneurological disorder or (d) preventing the disorder from occurring in asubject, tissue or cell predisposed to the neurological disorder or atrisk thereof, but has not yet been diagnosed with a protectivepharmacological and/or physiological effect so that the neurologicaldisorder does not develop or occur in the subject, tissue or cell.

The term “subject” as used herein refers to any animal, in particularmammals such as humans having a disease or condition which requirestreatment with the compound of formula I or II.

The term “administering” refers to providing the compound orpharmaceutical composition of the invention to a subject suffering fromor at risk of the diseases or conditions to be treated or prevented.

The term “neurological disorders” is used herein in its broadest senseand refers to disorders in which various cell types of the nervoussystem are degenerated and/or have been damaged as a result ofneurodegenerative disorders or injuries or exposures. In particular,compounds of formula I or II can be used for the treatment of resultingdisorders, in which damage to cells of the nervous system has occurereddue to surgical interventions, infections, exposure to toxic agents,tumours, nutritional deficits or metabolic disorders.

The term “neurodegenerative disorder” as used herein refers to anabnormaility in which neuronal integrity is threatened. Neuronalintegrity can be threatened when neuronal cells display decreasedsurvival or when the neurons can no longer propagate a signal.

Additionally, the compounds of formula I or II may also be used topotentiate the effects of other treatments, for example to potentiatethe neuroprotective effects of brain derived nerve growth factor.

The term “diseases characterized by metal imbalance” refers to a diseasewhereby a subject has either a too high or too low total amount ofmetal. This term also refers to a subject with a normal total amount ofmetal, but the metal is not correctly or is abnormally distributed.

The term “diseases characterized by the presence of oxidative stress”refers to a disease whereby biological constituents of a subject aredamaged by reactive oxygen species. It is particularly contemplated thatsuch constituents are damaged by reactive oxygen species such as thehydroxyl radical, hydrogen peroxide and superoxide produced in Fenton'sand similar reactions. In particular it is understood that metals suchas iron, copper, zinc, chromium, vanadium and cobalt are capable ofredox cycling in which a single electron may be accepted or donated bythe metal, facilitating oxidative reactions. Actual damage results whenthe oxidative species causes modifications of amino acids (e.g.meta-tyrosine and ortho-tyrosine formation from phenylalanine),carbohydrates and lipids (inducing peroxidation). In some cases suchmodification may cause a toxic gain of function or corruption of thebiological constituent substrate.

Reference to an “agent” includes combinations of two or more activeagents. A “combination” also includes multi-part such as a two-partcomposition where the agents are provided separately and given ordispensed separately or admixed together prior to dispensation. Forexample, a multi-part pharmaceutical pack may have two or more agentsseparately maintained. Hence, this aspect of the present inventionincludes combination therapy. Combination therapy includes theco-administration of an agent and another active such as achemotherapeutic compound, immunotherapeutic compound, cytokine, geneticmolecule and/or an anesthetic.

Dosages

The terms “effective amount” and “therapeutically effective amount” ofan agent as used herein mean a sufficient amount of the agent to providethe desired therapeutic or physiological or effect or outcome. Such aneffect or outcome includes inhibiting the growth or viability of cellsassociated with a glioma in the brain. Undesirable effects, e.g. sideeffects, are sometimes manifested along with the desired therapeuticeffect; hence, a practitioner balances the potential benefits againstthe potential risks in determining what is an appropriate “effectiveamount”. The exact amount required will vary from subject to subject,depending on the species, age and general condition of the subject, modeof administration and the like. Thus, it may not be possible to specifyan exact “effective amount”. However, an appropriate “effective amount”in any individual case may be determined by one of ordinary skill in theart using only routine experimentation.

The effective amount is deemed the amount required to inhibit the growthor viability of cells associated with a glioma. Effective amountsinclude from about 1 ng to about 1 g/subject administration. Theadministration may be a single dose or a series of divided doses.Amounts include from about 5 ng to about 800 mg/subject administration.Actual amounts include about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 ng or 200,300, 400, 500, 600, 700, 800, 900, 1000 ng or 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100 mg or 200, 300, 400, 500, 600, 700, 800, 900, 1000 mg per subject.

Pharmaceutical Compositions

The compositions of the present invention comprise at least one of thecompounds of formula I or II together with one or more pharmaceuticallyacceptable carriers and optionally other therapeutic agents. Eachcarrier must be pharmaceutically “acceptable” in the sense of beingcompatible with the other ingredients of the formulations and notinjurious to the subject. Carriers may include excipients and otheradditives such as diluents, detergents, coloring agents, wetting oremulsifying agents, pH buffering agents, preservatives, and the like.Compositions include those suitable for oral, rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal)administration. The compositions may conveniently be presented in unitdosage form and may be prepared by methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive ingredient with the carrier which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers, diluents, adjuvants and/or excipients or finelydivided solid carriers or both, and then if necessary shaping theproduct.

The compounds of formula I or II may be administered orally, topically,or parenterally in dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.The term parenteral as used herein includes subcutaneous injections,aerosol for administration to lungs or nasal cavity, intravenous,intramuscular, intrathecal, intracranial, injection, intraocular orinfusion techniques.

The present invention also provides suitable topical, oral, andparenteral pharmaceutical compositions for use in the novel methods oftreatment of the present invention. The compounds of the presentinvention may be administered orally as tablets, aqueous or oilysuspensions, lozenges, troches, powders, granules, emulsions, capsules,syrups or elixirs. The compositions for oral use may contain one or moreagents selected from the group of sweetening agents, flavoring agents,coloring agents and preserving agents in order to producepharmaceutically elegant and palatable preparations. Suitable sweetenersinclude sucrose, lactose, glucose, aspartame or saccharin. Suitabledisintegrating agents include corn starch, methylcellulose,polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.Suitable flavoring agents include peppermint oil, oil of wintergreen,cherry, orange or raspberry flavoring. Suitable preservatives includesodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methylparaben, propyl paraben or sodium bisulphite. Suitable lubricantsinclude magnesium stearate, stearic acid, sodium oleate, sodium chlorideor talc. Suitable time delay agents include glyceryl monostearate orglyceryl distearate. The tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets.

These excipients may be, for example, (1) inert diluents, such ascalcium carbonate, lactose, calcium phosphate or sodium phosphate; (2)granulating and disintegrating agents, such as corn starch or alginicacid; (3) binding agents, such as starch, gelatin or acacia; and (4)lubricating agents, such as magnesium stearate, stearic acid or talc.These tablets may be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. Coating may also be performed using techniques described inthe U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

The above compounds as well as the pharmaceutically-active agent usefulin the method of the invention can be administered, for in vivoapplication, parenterally by injection or by gradual perfusion over timeindependently or together. Administration may be intra-ocular,intravenously, intraarterial, intraperitoneally, intramuscularly,subcutaneously, intracavity, transdermally or infusion by, for example,osmotic pump. For in vitro studies the agents may be added or dissolvedin an appropriate biologically acceptable buffer and added to a cell ortissue.

Compositions for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's intravenousvehicles include fluid and nutrient replenishers, electrolytereplenishers (such as those based on Ringer's dextrose), and the like.Preservatives and other additives may also be present such as, forexample, anti-microbials, anti-oxidants, attenuating agents, growthfactors and inert gases and the like.

The present invention includes various pharmaceutical compositionsuseful for ameliorating disease. The pharmaceutical compositionsaccording to one embodiment of the invention are prepared by bringing anabove compound, analogs, derivatives or salts thereof, or combinationsof the above compounds and one or more pharmaceutically-active agentsinto a form suitable for administration to a subject using carriers,excipients and additives or auxiliaries. Frequently used carriers orauxiliaries include magnesium carbonate, titanium dioxide, lactose,mannitol and other sugars, talc, milk protein, gelatin, starch,vitamins, cellulose and its derivatives, animal and vegetable oils,polyethylene glycols and solvents, such as sterile water, alcohols,glycerol and polyhydric alcohols. Intravenous vehicles include fluid andnutrient replenishers. Preservatives include antimicrobial,anti-oxidants, attenuating agents and inert gases. Otherpharmaceutically acceptable carriers include aqueous solutions,non-toxic excipients, including salts, preservatives, buffers and thelike, as described, for instance, in Remington's PharmaceuticalSciences, 20th ed. Williams and Wilkins (2000) and The British NationalFormulary 43rd ed. (British Medical Association and Royal PharmaceuticalSociety of Great Britain, 2002; http://bnf.rhn.net), the contents ofwhich are hereby incorporated by reference. The pH and exactconcentration of the various components of the pharmaceuticalcompositions are adjusted according to routine skills in the art. SeeGoodman and Gilman's The Pharmacological Basis for Therapeutics (7thed., 1985).

The pharmaceutical compositions are preferably prepared and administeredin dose units. Solid dose units may be tablets, capsules andsuppositories. For treatment of a subject, depending on activity of thecompound, manner of administration, nature and severity of the disorder,age and body weight of the subject, different daily doses can be used.Under certain circumstances, however, higher or lower daily doses may beappropriate. The administration of the daily dose can be carried outboth by single administration in the form of an individual dose unit orelse several smaller dose units and also by multiple administration ofsubdivided doses at specific intervals.

The pharmaceutical compositions may be administered locally orsystemically in a therapeutically effective dose. Amounts effective forthis use will, of course, depend on the severity of the disease and theweight and general state of the subject. Typically, dosages used invitro may provide useful guidance in the amounts useful for in situadministration of the pharmaceutical composition, and animal models maybe used to determine effective dosages for treatment of the cytotoxicside effects. Various considerations are described, e.g., in Langer,Science, 249:1527, 1990.

Compositions for oral use may be in the form of hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin. They may alsobe in the form of soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, such as peanut oil, liquid paraffinor olive oil.

Aqueous suspensions normally contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspension. Suchexcipients may be (1) suspending agent such as sodiumcarboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;(2) dispersing or wetting agents which may be (a) naturally occurringphosphatide such as lecithin; (b) a condensation product of an alkyleneoxide with a fatty acid, for example, polyoxyethylene stearate; (c) acondensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethyleneoxycetanol; (d) a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand hexitol such as polyoxyethylene sorbitol monooleate, or (e) acondensation product of ethylene oxide with a partial ester derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to known methods using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The above compounds may also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles, and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine, orphosphatidylcholines.

The compounds may also be presented for use in the form of veterinarycompositions, which may be prepared, for example, by methods that areconventional in the art. Examples of such veterinary compositionsinclude those adapted for:

(a) oral administration, external application, for example drenches(e.g. aqueous or non-aqueous solutions or suspensions); tablets orboluses; powders, granules or pellets for admixture with feed stuffs;pastes for application to the tongue;

(b) parenteral administration for example by subcutaneous, intramuscularor intravenous injection, e.g. as a sterile solution or suspension; or(when appropriate) by intramammary injection where a suspension orsolution is introduced in the udder via the teat;

(c) topical applications, e.g. as a cream, ointment or spray applied tothe skin; or

(d) intravaginally, e.g. as a pessary, cream or foam.

EXAMPLES

The present invention is further described by the following non-limitingExamples.

Example 1

Scheme 1

Substituted 9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-ones can be preparedby the synthetic route depicted in Scheme 1. Starting from an esterintermediate 1-1, reaction with LDA at low temperature generates theenolate anion which is quenched with ethyl formate to afford thealdehyde 1-2. Heating the aldehyde to reflux with a 3-hydroxypyridinol1-3 generates an ester 1-4. Cyclisation of 1-4 in boiling acetic acidprovides after crystallization, the desired target compounds 1-5 (Scheme1).

in which R³ is C₁₋₄alkyl optionally interrupted with O, C₅₋₆cycloalkylor benzyl optionally fused with a 5 membered O containing heterocyclyl;R⁶ is Cl or Br; andR⁷ is 1.

Compound 1621 Ethyl-2-cyclohexyl-3-oxopropanoate (1-2)

Ethyl-2-cyclohexyl acetate (7.5 g, 44 mmol) was dissolved in anhydrousTHE (20 mL) and then added to a solution of LDA (28.6 mL, 2.0 M solutionin heptane/THF/ethylbenzene) at −78° C. After stirring at thistemperature for 1 h, ethyl formate (4.8 mL, 59 mmol) was added and thereaction was warmed to rt over 3 h. The reaction was quenched carefullywith H₂O then THE was removed on a rotary evaporator. The mixture wasthen extracted with petroleum spirits 60-80° C. (×3). The aqueous layerwas then acidified to pH 2 with conc. HCl and extracted into CH₂Cl₂(×2). The organic extracts were dried over Na₂SO₄, filtered andconcentrated to furnish the desired aldehyde 1-2 as an orange oil (5.65g, 65%). ¹H NMR (500 MHz, CDCl₃) δ 1.14 (m, 4H), 1.31 (m, 4H), 1.76 (m,2H), 2.18 (m, 2H), 3.00 (m, 1H), 4.24 (m, 2H), 7.01 (d, J=12.5 Hz, 1H),9.70 (dd, J=4, 1 Hz, 1H), 11.66 (d, J=12.5 Hz, 1H).

E:Z-Ethyl-2-cyclohexyl-3-(3-hydroxypyridin-2ylamino)acrylate (1-4)

The aldehyde 1-2 (4.0 g, 20.2 mmol) was dissolved in EtOH (100 mL) towhich was added 2-amino-3-hydroxypyridine 1-3 (2.0 g, 18.2 mmol) and thereaction was heated to reflux for 3 h. Solvent was removed in vacuo toprovide a brown solid (5.4 g, quantitative yield). Crude NMR showed amixture of E:Z isomers 1-4 and the material was carried forward with nopurification.

3-Cyclohexyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (1-5) (1621)

The keto-enol mixture 1-4 (5.4 g, 18.6 mmol) was dissolved in glacialAcOH (100 ml) and the resulting dark brown solution was heated to refluxfor 3 h. Solvent was removed in vacuo to give a yellow/brown solid. Thecrude material was dissolved in hot EtOH (100 mL) and left to standovernight. The resulting yellow solid that formed was collected byfiltration and dried to afford3-Cyclohexyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one 1-5 as yellowplates (2.8 g, 62%). ¹H NMR 500 MHz, CDCl₃) δ 1.31 (m, 1H), 1.47 (m,4H), 1.78 (m, 1H), 1.87 N (m, 2H), 1.97 (m, 2H), 2.93 (m, 1H), 7.03 (t,J=7.5 Hz, 1H), 7.08 (dd, J=7.5, 1.5 Hz, 1H), 8.13 (s, 1H), 8.55 (dd,J=7.5, 1.5 Hz, 1H). HPLC: t_(R)=9.39 min (98.1%), MS m/z 245.09 [M+H]⁺

TABLE 1 Compounds prepared according to Example 1 (Scheme 1) CompoundStructure MW Proton NMR MS 1235

m/z 238.68 [M + H]⁺ 1607

238.67 ¹H (500 MHz, CDCl₃) δ 1.00 (t, J = 7.5 Hz, 3H), 1.70 (sext, J =7.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 6.5 (br s, 1H), 7.08 (d, J = 2.0Hz, 1H), 8.11 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H) m/z 239.01 [M + H]⁺ 1621

244.30 ¹H NMR 500 MHz, CDCl₃) δ 1.31 (m, 1H), 1.47 (m, 4H), 1.78 (m,1H), 1.87 (m, 2H), 1.97 (m, 2H), 2.93 (m, 1H), 7.03 (t, J = 7.5 Hz, 1H),7.08 (dd, J = 7.5, 1.5 Hz, 1H), 8.13 (s, 1H), 8.55 (dd, J = 7.5, 1.5 Hz,1H) m/z 245.01 [M + H]⁺ 1622

278.31 ¹H NMR (500 MHz, CDCl₃) δ 1.29 (m, 1H), 1.46 (m, 4H), 1.79 (m,1H), 1.87 (m, 2H), 1.96 (m, 2H), 2.93 (m, 1H), 5.97 (br s, 1H), 7.06 (d,J = 2.0 Hz, 1H), 8.10 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H) m/z 279.0 [M +H]⁺ 1623

230.26 ¹H NMR (500 MHz, d6- DMSO) δ 1.66 (m, 4H), 1.78 (m, 2H), 1.95 (m,2H), 3.14 (m, 1H), 7.14 (m, 2H), 8.23 (s, 1H), 8.46 (dd, J = 7.0, 1.5Hz, 1H). m/z 231.1 [M + H]⁺ 1624

264.71 ¹H NMR (500 MHz, d6- DMSO) δ 1.66 (m, 4H), 1.77 (m, 2H), 1.98 (m,2H), 3.13 (m, 1H), 7.15 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 8.45 (d, J =2.0 Hz, 1H) m/z 265.0 [M + H]⁺ 1643

238.7 ¹H NMR (500 MHz, d₆- DMSO) δ 049 (d, J = 7.0 Hz, 6H), 2.37 (sept,J = 7.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.71 (d, J =2.0 Hz, 1H). m/z 239.1 [M + H]⁺ 1599

283.1 ¹H NMR (500 MHz, d₆- DMSO) δ 0.90 (t, J = 7.5 Hz, 3H), 1.59 (sext,J = 7.5 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 7.24 (d, J = 1.5 Hz, 1H),8.23 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H) m/z 283.0 [M + H]⁺ 1611

364.6 ¹H NMR (500 MHz, CDCl₃) δ 1.00 (t, J = 7.5 Hz, 3H), 1.70 (sext, J= 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 5.31 (s, 1H), 8.08 (s, 1H),8.65 (s, 1H) m/z 364.9 [M + H]⁺ 1650

282.3 ¹H NMR (500 MHz, d₆- DMSO) δ 6.60 (s, 2H), 6.99 (d, J = 8 Hz, 1H),7.23-7.28 (m, 2H), 7.33 (dd, J = 1.5, 8.5 Hz, 1H), 7.43 (d, J = 1.5 Hz,1H), 8.53 (s, 1H), 8.61 (dd, J = 1.5, 7.0 Hz, 1H). m/z 283.0 [M + H]⁺1674

252.3 ¹H NMR (500 MHz, d₆- DMSO) δ 3.40 (s, 2H), 7.18 (m, 3H), 7.25 (m,4H), 8.32 (s, 1H), 8.46 (s, 1H) m/z 253.1 [M + H]⁺ 1675

286.7 ¹H NMR (500 MHz, d₆- DMSO) δ 3.90 (s, 2H), 7.16 (m, 2H), 7.27 (m,4H), 8.32 (s, 1H), 8.44 (s, 1H) m/z 287.1 [M + H]⁺ 1685

220.2 ¹H NMR (400 MHz, d6- DMSO) δ 2.94 (t, J = 5.2 Hz, 2H), 3.36 (s,3H), 3.69 (t, J = 5.2 Hz, 2H), 7.06 (t, J = 6.0 Hz, 1H), 7.11 (d, J =6.0 Hz, 1H), 8.21 (s, 1H), 8.56 (d, J = 7.0 Hz, 1H). m/z 221.2 [M + H]⁺1686

254.7 ¹H NMR (400 MHz, d6- DMSO) δ 2.92 (t, J = 4.8 Hz, 2H), 3.46 (s,3H), 3.72 (t, J = 4.8 Hz, 2H), 7.09 (d, J = 2.0 Hz, 1H), 7.11 (d, J =6.0 Hz, 1H), 8.18 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H) m/z 255.1 [M + H]⁺

Example 2

Substituted aryl and heteroaryl9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-ones can be prepared by taking a9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one 1-5 in which R⁷ is Hsynthesized in Example 1 shown in Scheme 1 above and iodinating at theortho position to the phenol using iodine and hydrogen peroxide toafford 2-1 (Scheme 2). After protection of the phenol to provide 2-2, aSuzuki coupling reaction can be carried out with Pd(PPh₃)₄ as catalystand commercially available boronic acids R⁷B(OH)₂ or boronate estersR⁷B(OR⁵)₂ to afford aryl and heteroaryl compounds 2-3. Deprotection ofthe isopropoxy group in 2-3 by the action of HBr gives the targetcompounds 2-4 Scheme 2).

in which R³ is C₁₋₄alkyl or C(O)NHC₁₋₄alkyl;R⁶ is Cl; andR⁷ is 5 or 6 membered optionally substituted heterocyclyl, optionallysubstituted phenyl or I.

Compound 16297-Chloro-9-hydroxy-8-iodo-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (2-1)

7-Chloro-9-hydroxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one 1-4 (500 mg,2.1 mmol) was dissolved in EtOH (20 mL) and then treated with iodine(585 mg, 2.3 mmol) and 30% aq H₂O₂ (0.24 mL, 2.35 mmol) and the reactionwas stirred for 48 h. The resulting precipitate was filtered, washedwith EtOH and then dried giving the iodo compound 2-1 as a yellow powder(520 mg, 68%). ¹H NMR (500 MHz, CDCl₃) δ 1.00 (t, J=7.5 Hz, 3H), 1.70(sext, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 5.31 (s, 1H), 8.81 (s,1H), 8.65 (s, 1H).

7-Chloro-8-iodo-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one(2-2)

7-Chloro-9-hydroxy-8-iodo-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (450mg, 1.2 mmol) was dissolved in anhydrous DMF (10 mL) to which was thenadded K₂CO₃ (511 mg, 3.7 mmol) and 2-bromopropane (290 μL, 3.08 mmol)and the resulting dark mixture was stirred at 60° C. under argon o/n.The reaction was diluted with EtOAc (50 mL) and H₂O (70 mL) and theEtOAc layer was separated. The aqueous layer was further extracted intoEtOAc (×2) and the combined organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated to afford the isopropylether 2-2 as a yellow solid (230 mg, 46%). ¹H NMR (500 MHz, CDCl₃) δ0.99 (t, J=7.5 Hz, 3H), 1.44 (d, J=6.0 Hz, 6H), 1.69 (sext, J=7.5 Hz,2H), 2.61 (t, J=7.5 Hz, 2H), 5.51 (sept, J=6.0 Hz, 1H), 8.15 (s, 1H),8.92 (s, 1H).

7-Chloro-8-(pyridine-3-yl)-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one(2-3)

7-Chloro-8-iodo-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one2-2 (100 mg, 0.25 mmol) 3-pyridyl boronic acid (37 mg, 0.30 mmol) weredissolved in DMF (5 mL) followed by the addition of 2M K₂CO₃ (0.5 mL, 1mmol)). The solution was degassed via argon sparge/sonication thenPd(PPh₃)₄ (15 mg, 0.013 mmol) was added and the reaction was heated to100° C. for 18 h. The reaction was diluted with EtOAc and filteredthrough celite rinsing with EtOAc. The solvent was removed in vacuo andthe residue was purified by flash chromatography eluting with 40%EtOAc/petroleum ether 40-60° C., giving a gummy solid. A second columneluting with 10%-20% ether/CH₂Cl₂ afforded the desired pyridine 2-3 as awhite solid (53 mg, 60%). ¹H NMR (500 MHz, CDCl₃) δ1.01 (t, J=7.5 Hz,3H), 1.05 (d, J=6.0 Hz, 6H), 1.72 (sext, J=7.5 Hz, 2H), 2.66 (t, J=7.5Hz, 2H), 4.93 (sept, J=6.0 Hz, 1H), 7.45 (ddd, J=8, 5, 0.5 Hz, 1H), 7.77(dt, J=8.0, 2.0 Hz, 1H), 8.23 (s, 1H), 8.68 (d, J=1.5 Hz, 1H), 8.71 (dd,J=5.0, 1.5 Hz, 1H), 9.02 (s, 1H).

7-Chloro-9-hydroxy-3-propyl-8-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidine-4-one(2-4) (1629)

7-Chloro-8-(pyridine-3-yl)-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one2-3 (50 mg, 0.14 mmol) was added to 48% aq HBr (3 mL) and heated to 120°C. for 1.5 h. Upon cooling the resulting yellowish solution wasneutralized with sat. aq. NaHCO₃. The aqueous layer was extracted intoCH₂Cl₂ (×3) and the organic layer was dried over Na₂SO₄, filtered andconcentrated to a afford7-Chloro-9-hydroxy-propyl-8-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidine-4-one(2-4) as a light green powder (38 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ1.02 (t, J=7.5 Hz, 3H), 1.72 (sext, J=7.5 Hz, 2H), 2.67 (t, J=7.5 Hz,2H), 7.47 (dd, J=7.5, 5.0 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 8.14 (s, 1H),8.71 (d, J=5.0 Hz, 1H), 8.74 (s, 1H), 8.75 (br s, 1H). HPLC: t_(R)=7.99min (91.7%). MS: m/z 316.1 [M+H]⁺.

TABLE 2 Compounds prepared according to Example 2 (Scheme 2) CompoundStructure MW NMR MS 1596

281.31 ¹H NMR (500 MHz, d6- DMSO δ 1.27 (d, J = 7.0 Hz, 6H), 3.14 (m,1H), 7.48 (d, J = 7.0 Hz, 1H), 7.54 (m, 1H), 8.20 (d, J = 8.0 Hz, 1H),8.25 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 4 Hz, 1H), 9.00 (s,1H) m/z 282.1 [M + H]⁺ 1597

326.39 ¹H NMR (500 MHz, d6- DMSO) δ 0.88 (d, J = 6.5 Hz, 6H), 1.28 (d, J= 7.0 Hz, 6H), 2.17 (m, 1H), 3.14 (m, 1H), 4.02 (d, J = 7.5 Hz, 2H),7.63 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H)m, 8.44 (s, 1H), 8.46(d, J = 7.5 m/z 327.1 [M + H]⁺ Hz, 1H). 1600

299.32 ¹H NMR (500 MHz, d6- DMSO) δ 1.27 (d, J = 7.0 Hz, 6H), 2.19 (s,3H), 2.35 (s, 3H), 3.14 (m, 1H), 7.22 (d, J = 7.5 Hz, 1H), 0, 8.24 (s,1H), 8.48 (d, J = 7.5 Hz, 1H). m/z 300.1 [M + H]⁺ 1601

312.37 ¹H NMR (500 MHz, d6- DMSO) δ 0.85 (d, J = 7.0 Hz, 3H), 1.26 (d, J= 7.0 Hz, 6H), 3.11 (sept, J = 7.0 Hz, 1H), 4.15 (t, J = 7.0 Hz, 2H),7.61 (d, J = 7.5 Hz, 1H), 8.18 (s, 1H), 8.20 (s, 1H), 8.43 (s, 1H), 8.45(d, J = 7.5 Hz, m/z 313.1 [M + H]⁺ 1H). 1602

284.31 ¹H NMR (500 MHz, CDCl₃) δ 1.34 (d, J = 7.0 Hz, 6H), 3.30 (sept, J= 7.0 Hz, 1H), 3.93 (s, 3H), 6.49 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H),7.61 (s, 1H), 8.17 (s, 1H), 8.58 (d, J = 7.5H, 1H). m/z 285.1 [M + H]⁺1603

299.32 ¹H NMR (500 MHz, d6- DMSO) δ 0.91 (t, J = 7.5 Hz, 6H), 1.81 (m,2H), 2.19 (s, 3H), 2.35 (s, 3H), 7.29 (d, J = 7.5 Hz, 1H), 0, 8.26 (s,1H), 8.51 (d, J = 7.5 Hz, 1H) m/z 300.2 [M + H]⁺ 1629

315.75 ¹H NMR (500 MHz, CDCl₃) δ 1.02 (t, J = 7.5 Hz, 3H), 1.72 (sext, J= 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 7.47 (dd, J = 7.5, 5.0 Hz, 1H),7.84 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 8.71 (d, J = 5.0 Hz, 1H), 8.74(s, 1H), 8.75 (br s, 1H) m/z 316.1 [M + H]⁺ 1630

333.7 ¹H NMR (500 MHz, CDCl₃) δ 1.02 (t, J = 7.5 Hz, 3H), 1.72 (sext, J= 7.5 Hz, 2H), 2.23 (s, 3H), 2.36 (s, 3H), 2.66 (t, J = 7.5 Hz, 2H),8.13 (s, 1H), 8.72 (s, 1H) m/z 334.1 [M + H]⁺ 1633

284.3 ¹H NMR (500 MHz, d6- DMSO) δ 1.26 (d, J = 7.0 Hz, 6H), 3.11 (m,1H), 3.93 (s, 3H), 7.61 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 8.19 (s, 1H),8.41 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H)′ m/z 285.1 [M + H]⁺ 1639

298.3 ¹H NMR (500 MHz, d6- DMSO) δ 0.92 (t, J = 7.5 Hz, 3H), 1.61 (q, J= 7.5 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 7.34 (app t, J = 8.5 Hz, 2H),7.41 (d, J = 7.5 Hz, 1H), 7.86 (m, 2H), 8.26 (s, 1H), 8.48 (d, J = 7.5Hz, 1H) m/z 299.1 [M + H]⁺ 1641

281.3 ¹H NMR (500 MHz, CDCl₃) δ 0.92 (t, J = 7.0 Hz, 3H), 1.62 (q, J =7.0 Hz, 2H), 2.57 (t, J = 7.0 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H), 8.07(m, 1H), 8.24 (s, 1H), 8.37 (d, J = 7.5 Hz, 1H), 8.85 (d, J = 5.5 Hz,1H), 8.91 (d, J = 8.0 Hz, 1H), 9.51 (s, 1H). m/z 282.1 [M + H]⁺ 1648

298.3 ¹H NMR (500 MHz, d6- DMSO) δ 0.91 (t, J = 7.5 Hz, 3H), 1.60 (sext,J = 7.5 Hz, 2H), 2.13 (s, 6H), 2.54 (t, J = 7.5 Hz, 2H), 7.15 (d, J =7.0 Hz, 1H), 8.23 (s, 1H), 8.44 (d, J = 7.0 Hz, 1H). m/z 299.2 [M + H]⁺1651

298.3 ¹H NMR (500 MHz, d6- DMSO) δ 1.26 (d, J = 6.5 Hz, 6H), 2.14 (s,6H), 3.13 (sept, J = 6.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 8.22 (s,1H), 8.47 (d, J = 7.5 Hz, 1H). m/z 299.1 [M + H]⁺ 1652

286.4 ¹H NMR (500 MHz, d6- DMSO) δ 1.33 (d, J = 7.0 Hz, 6H), 3.26 (sept,J = 7.0 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.46 (dd, J = 4.0, 2.0 Hz,1H), 7.19 (d, J = 4.0 Hz, 1H), 8.12 (s, 1H), 8.16 (s, 1H), 8.56 (d, J =7.5 Hz, 1H). m/z 287.0 [M + H]⁺ 1653

270.3 ¹H NMR (500 MHz, d6- DMSO) δ 1.32 (d, J = 7.0 Hz, 6H), 3.26 (sept,J = 7.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H),7.57 (t, J = 2.0 Hz, 1H), 8.15 (s, 1H), 8.30 (s, 1H), 8.56 (d, J = 7.5Hz, 1H). m/z 271.1 [M + H]⁺ 1654

284.3 ¹H NMR (400 MHz, CDCl₃) δ 1.32 (d, J = 7.2 Hz, 6H), 3.26 (sept, J= 7.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H), 7.57(d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H). m/z 285.1[M + H]⁺ 1655

281.3 ¹H NMR (500 MHz, d6- DMSO) δ 1.27 (d, J = 6.5 Hz, 6H), 3.12 (sept,J = 6.5 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 8.16 (s, 1H), 8.17 (br m,2H), 8.31 (d, J = 7.0 Hz, 1H), 8.73 (d, J = 6.0 Hz, 1H) m/z 282.1 [M +H]⁺ 1659

298.3 ¹H NMR (400 MHz, d6- DMSO) δ 0.91 (t, J = 7.2 Hz, 3H), 1.36 (sext,J = 7.2 Hz, 2H), 1.51 (quin, J = 7.6 Hz, 2H), 3.35 (m, 2H), 7.45 (d, J =7.2 Hz, 1H), 8.60 (d, J = 7.2 Hz, 1H), 8.96 (s, 1H), 9.01 (m, 1H). m/z299.2 [M + H]⁺, 282.3 [M − 17]⁺ 1660

355.4 ¹H NMR (400 MHz, d6- DMSO) δ 0.91 (t, J = 7.6 Hz, 3H), 1.36 (m,2H), 1.51 (m, 2H), 3.36 (m, 2H), 7.36 (m, 2H), 7.66 (d, J = 7.2 Hz, 1H),7.90 (m, 2H), 8.70 (d, J = 7.2 Hz, 1H), 8.99 (m, m/z 356.1 [M + H]⁺ 1H),9.02 (s, 1H). 1668

348.3 ¹H NMR (400 MHz, d6- DMSO) δ 1.28 (d, J = 7.0 Hz, 6H), 3.16 (sept,J = 7.0 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H),7.67 (t, J = 7.5 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.87 (d, J = 7.5 Hz,1H), 8.26 (s, 1H), 8.50 (d, J = 7.5 Hz, 1H) m/z 349.1 [M + H]⁺ 1671

296.4 ¹H NMR (500 MHz, d6- DMSO) δ 1.28 (d, J = 7.0 Hz, 6H), 2.17 (s,3H), 3.15 (sept, J = 7.0 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.24 (d, J =7.0 Hz, 1H), 7.28 (m, 1H), 7.32 (m, 2H), 8.25 (s, 1H), 8.50 (d, J = 7.5Hz, 1H). 1680

281.3 ¹H NMR (400 MHz, d6- DMSO) δ 0.92 (t, J = 7.2 Hz, 3H), 1.62 (m,2H), 2.56 (m, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 6.0 Hz, 2H),8.23 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.71 (d, J = 6.0 Hz, 2H). m/z282.1 [M + H]⁺ 1681

316.3 ¹H NMR (400 MHz, d6- DMSO) δ 0.92 (t, J = 7.2 Hz, 3H), 1.62 (m,2H), 2.56 (m, 2H), 7.31 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.61 (m, 2H),8.26 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H) m/z 317.1 [M + H]⁺ 1683

323.4 ¹H NMR (400 MHz, CDCl₃) δ 0.937 (t, J = 7.2 Hz, 3H), 1.04 (s, 3H),1.04 (d, J = 3.2 Hz, 6H), 1.66 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 4.82(s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 7.55 (dd, J = 4.4, 1.6 Hz, 2H), 8.19(s, 1H), 8.69 (dd, J = 4.4, 1.6 Hz, 2H), 8.82 (d, J = 7.2 Hz, 1H). m/z324.2 [M + H]⁺ 1684

372.2 ¹H NMR (500 MHz, d6- DMSO) δ 1.24 (d, J = 4.0 Hz, 6H), 1.32 (s,6H), 3.07 (m, 1H), 5.31 (m, 1H), 7.57 (d, J = 7.5 Hz, 1H), 8.23 (s, 1H),8.42 (d, J = 7.5 Hz, 1H) m/z 373.1 [M + H]⁺

Example 3

Substituted methylamino compounds can be prepared from9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-ones synthesized in Scheme 1above, adapting a procedure from Chemistry of Heterocyclic Compounds,1992, 28, 1425-1431. Reaction of commercially available aminals with9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-ones 1-5 provided the desiredcompounds 3-1 (Scheme 3).

in which R³ is C₅₋₆cycloalkyl, C₁₋₄alkyl optionally interrupted with Oor benzyl;R⁷ is CH₂NR¹⁰R¹⁰ in which R⁹ and R¹⁰ are C₁₋₂alkyl or together with theN to which they are attached from morpholinyl.

Compound 16273-Cyclopentyl-8-(dimethylamino)methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one(3-1)

A solution of cyclopentyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (137mg, 0.60 mmol) 1-5 in anhydrous toluene (4 mL) was treated withN,N,N,N-tetramethylmethylenediamine (240 mL, 1.76 mmol) for 4 h. Thereaction was cooled, concentrated and the resulting solid wascrystallized from hot acetonitrile to afford the desired amine 3-1 as apale green solid (50 mg, 29%). ¹H NMR (500 MHz, d6-DMSO) 1.71 (m, 4H),1.84 (m, 2H), 1.66 (m, 2H), 2.07 (m, 2H), 2.41 (s, 6H), 3.23 (m, 1H),3.72 (s, 2H), 6.84 (d, J=7.5 Hz, 1H), 8.26 (s, 1H), 8.57 (d, J=7.5 Hz,1H). HPLC: tR=7.64 min (92.6%). MS: m/z 288.1 [M+H]⁺

TABLE 3 Compounds prepared according to Example 3 (Scheme 3) CompoundStructure MW NMR MS 1627

287.4 ¹H NMR (500 MHz, d6-DMSO) δ 1.71 (m, 4H), 1.84 (m, 2H), 1.66 (m,2H), 2.07 (m, 2H), 2.41 (s, 6H), 3.23 (m, 1H), 3.72 (s, 2H), 6.84 (d, J= 7.5 Hz, 1H), 8.26 (s, 1H), 8.57 (d, J = 7.5 Hz, 1H) m/z 288.1 [M + H]⁺1631

261.3 ¹H NMR (500 MHz, CDCl₃) δ 0.99 (t, J = 7.5 Hz, 3H), 1.70 (sext, J= 7.5 Hz, 2H), 2.41 (s, 6H), 2.64 (t, J = 7.5 Hz, 2H), 3.73 (s, 2H),6.85 (d, J = 7.5 Hz, 1H), 8.21 (s, 1H), 8.57 (d, J = 7.5 Hz, m/z 262.2[M + H]⁺ 1H); 1632

261.3 ¹H NMR (500 MHz, d6-DMSO) δ 1.32 (d, J = 7.0 Hz, 6H), 3.27 (m,1H), 3.73 (s, 2H), 6.85 (d, J = 7.5 Hz, 1H), 8.24 (s, 1H), 8.57 (d, J =7.5 Hz, 1H). m/z 262.2 [M + H]⁺ 1640

329.3 ¹H NMR (500 MHz, CDCl3) δ 1.71 (m, 4H), 1.84 (m, 2H), 2.08 (m,2H), 2.62 (m, 4H), 3.26 (quintet, 1H), 3.78 (m, 6H), 6.94 (d, J = 7.5Hz, 1H), 8.22 (s, 1H), 8.56 (d, J = 7.5 Hz, 1H). m/z 330.2 [M + H]⁺ 1642

301.4 ¹H NMR (500 MHz, CDCl₃) δ 1.27 (m, 1H), 1.48 (m, 4H), 1.77 (m,1H), 1.85 (m, 2H), 1.95 (m, 2H), 2.40 (s, 6H), 2.92 (m, 1H), 3.72 (s,2H), 6.83 (d, J = 7.5 Hz, 1H), 8.21 (s, 1H), 8.56 (d, J = 7.5 Hz, 1H).m/z 302.2 [M + H]⁺ 1645

303.4 ¹H NMR (500 MHz, CDCl₃) δ 0.98 (t, J7.5 Hz, 3H), 1.69 (sext, J =7.5 Hz, 2H), 2.62 (m, 6H), 3.77 (s, 6H), 6.94 (d, J = 7.0 Hz, 1H), 8.18(s, 1H), 8.56 (d, J = 7.0 Hz, 1H). m/z 304.2 [M + H]⁺ 1647

289.4 ¹H NMR (400 MHz, CDCl₃) δ 0.98 (t, J = 7.2 Hz, 3H), 1.18 (t, J =7.2 Hz, 6H), 1.69 (sext, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.71(q, J = 7.2 Hz, 4H), 3.87 (s, 2H), 6.76 (d, J = 7.2 Hz, 1H), 8.22 (s,1H), m/z 290.2 [M + H]⁺ 8.55 (d, J = 7.2 Hz, 1H). 1656

303.4 ¹H NMR (500 MHz, d6-DMSO) δ 1.31 (d, J = 7 Hz, 6H), 2.61 (m, 4H),3.27 (sept, J = 7 Hz, 1H), 3.76 (m, 6H), 6.95 (d, J = 7.5 Hz, 1H), 8.20(s, 1H), 8.56 (d, J = 7.5 Hz, 1H) m/z 304.2 [M + H]⁺ 1679

275.4 ¹H NMR (400 MHz, CDCl₃) δ 0.94 (t, J = 7.2 Hz, 3H), 1.39 (sext, J= 7.2 Hz, 2H), 1.62 (quin, J = 7.2 Hz, 2H), 2.41 (s, 6H), 2.85 (t, J =7.2 Hz, 1H), 3.73 (s, 2H), 6.83 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 8.56(d, m/z 276.2 [M + H]⁺ J = 7.2 Hz, 1H), 1691

277.3 ¹H NMR (400 MHz, d6-DMSO) δ 2.76 (s, 6H), 2.82 (t, J = 6.5 Hz,2H), 3.24 (s, 3H), 3.56 (t, J = 6.5 Hz, 2H), 4.39 (s, 2H), 7.47 (d, J =7.0 Hz, 1H), 8.28 (s, 1H), 8.48 (d, J = 7.0 Hz, 1H). m/z 278.2 [M + H]⁺1693

309.4 ¹H NMR (500 MHz, d6-DMSO) δ 2.22 (s, 6H), 3.58 (s, 2H), 3.88 (s,2H), 7.22 (m, 6H), 8.30 (s, 1H), 8.42 (s, J = 5.0 Hz, 1H) m/z 310.2 [M +H]⁺ 1706

319.4 ¹H NMR (400 MHz, d6-DMSO) δ 2.62 (s, 4H), 2.92 (t, J = 6.8 Hz,2H), 3.65 (s, 3H), 3.67 (t, J = 6.8 Hz, 2H), 3.68 (m, 4H), 3.78 (s, 2H),6.97 (d, J = 7.6 Hz, 1H), 8.25 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H). m/z320.2 [M + H]⁺

Example 4

Substituted triazole compounds can be prepared from compounds 1-5 inScheme 1. Protection of 1-4 to give 4-1 followed by Sonagashira couplingprovides trimethylsilyacetylene compounds 4-2. Removal of the silanegroup under basic conditions affords the acetylenes 4-3. Compound 4-3 isallowed to react with a known azide in the presence of a Cu(II)catalyst. Subsequent 1,3-dipolar cycloaddition (Click chemistry)proceeds smoothly to generate substituted triazoles 4-4. Finally,deprotection of 4-4 affords the target compounds 4-5 (Scheme 4). Note:azides are prepared according to a literature procedure described inSynthesis 1997, 4, 413-414 (scheme 4).

in which R³ is C₁₋₄alkyl;R¹¹ is Br; andR¹² is benzyl or cyclopentyl.

Compound 16167-Bromo-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (4-1)

7-Bromo-9-hydroxy-3-propyl-4H-pyridon[1,2-a]pyrimidin-4-one 1-5 (2.0 g,7.1 mmol) was dissolved in anhydrous DMF (30 mL) then treated with K₂CO₃(2.93 g, 2.1 mmol) followed by 2-brompropane (1.65 mL, 17.7 mmol) andthe reaction was stirred at 60° C. o/n. Volatiles were removed in vacuoand the residue was taken up in H₂O (50 mL) and EtOAc (50 mL). The EtOAclayer was separated and the aqueous layer was further extracted intoEtOAc (2×50 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, concentrated and purified by flashchromatography eluting with 10% EtOAc/petroleum spirits 40-60° C. toafford the isopropyl ether 4-1 as a brown oil (1.50 g, 65%). ¹H NMR (500MHz, CDCl₃) 0.98 (t, J=7.5 Hz, 3H), 1.53 (d, J=6.0 Hz, 6H), 1.68 (sext,J=7.5 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 4.73 (sept, J=6.0 Hz, 1H), 6.96(d, J=1.5 Hz, 1H), 8.24 (s, 1H), 8.80 (d, J=1.5 Hz, 1H).

9-Isopropoxy-3-propyl-7-((trimethylsoliyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one(4-2)

7-Bromo-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one 4-1 (1.45g, 4.5 mmol) was dissolved in anhydrous THE (60 mL) and diisopropylamine(5 mL, 35.7 mmol). The solution was degassed via argon sparge andsonication then the following reagents were introduced into the reactionvessel. PdCl₂ (PPh₃)₂ (188 mg, 0.27 mmol), CuI (17 mg, 0.09 mmol) andTMS acetylene (1 mL, 7.08 mmol) then the reaction was heated to 70° C.for 2 h. The reaction was filtered through a small pad of silica gelwashing with EtOAc. The filtrate was concentrated and the residue waspurified by flash chromatography eluting with petroleum spirits 40-60°C.-40% EtOAc/petroleum spirits 40-60° C. to provide the silane 4-2 as ayellow solid (1.40 g, 92%). ¹H NMR (500 MHz, CDCl₃) δ 0.29 (s, 9H), 0.98(t, J=7.5 Hz, 3H), 1.52 (d, J=6.0 Hz, 6H), 1.68 (sext, J=7.5 Hz, 2H),2.62 (t, J=7.5 Hz, 2H), 4.75 (sept, J=6.0 Hz, 1H), 6.85 (d, J=1.5 Hz,1H), 8.22 (s, 1H), 8.79 (d, J=1.5 Hz, 1H).

7-Ethynyl-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (4-3)

9-Isopropoxy-3-propyl-7-((trimethylsoliyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one4-2 (1.40 g, 4.1 mmol) was dissolved in MeOH (20 mL), then K₂CO₃ (622mg, 4.5 mmol) was added to the reaction. After stirring at rt for 15min, the reaction diluted with ether (20 mL) and H₂O (20 mL). Theorganic layer was separated and the aqueous layer was further extractedinto ether (2×20 mL). Combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to afford the acetylene 4-3as an orange solid (950 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ0.98 (t,J=7.5 Hz, 3H), 1.53 (d, J=6.0 Hz, 6H), 1.68 (sext, J=7.5 Hz, 2H), 2.63(t, J 7.5 Hz, 2H), 3.20 (s, 1H), 4.74 (sept, J=6.0 Hz, 1H), 6.87 (d,J=1.5 Hz, 1H), 8.23 (s, 1H), 8.83 (s, J=2.0 Hz, 1H).

7-(1-Benzyl-1H-1,2,3-triazol-4-yl)-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one(4-4)

7-Ethynyl-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (4-3)(200 mg, 0.74 mmol) was dissolved in EtOH (5 mL), then benzyl azide (125mg, 0.94 mmol) in EtOH (5 mL) was added followed by H₂O (10 mL). To thereaction was then added CuSO₄.5H₂O (123 μL, 0.3M aqueous solution, 5 mol%), and sodium ascorbate (148 μL, 1M aqueous solution, 20 mol %) and thereaction was stirred in the dark for 24 h. The reaction was diluted withH₂O and extracted into CH₂Cl₂ (×3). The organic layer was washed withbrine, dried over Na₂SO₄, filtered, concentrated and purified by flashchromatography eluting with 10-40% EtOAc/petroleum spirits 40-60° C. tofurnish the triazole 4-4 as a white solid (308 mg, quantitative yield).¹H NMR (500 MHz, CDCl₃) δ0.98 (t, J=7.5 Hz, 3H), 1.56 (d, J=6.0 Hz, 6H),1.68 (sext, J=7.5 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 4.92 (sept, J=6.0 Hz,1H), 5.62 (s, 2H), 7.38 (m, 5H), 7.72 (d, J=1.0 Hz, 1H), 7.83 (s, 1H),8.25 (s, 1H), 8.86 (d, J=2.0 Hz, 1H).

7-(1-Benzyl-1H-1,2,3-triazol-4-yl)-9-hydroxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one(4-5)(1616)

7-(1-Benzyl-1H-1,2,3-triazol-4-yl)-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one4-4 (300 mg, 0.74 mmol) was added to 48% aqueous HBr (4 mL) and themixture was heated to reflux for 1 h. After cooling the reaction wasneutralized with sat. aq. NaHCO₃ then extracted into CH₂Cl₂ (×3). Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford the product 4-5 as an off-white powder (256 mg,95%). ¹H NMR (500 MHz, CDCl₃) 1.00 (t, J=7.5 Hz, 3H), 1.70 (sext, J=7.5Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 5.61 (s, 2H), 7.39 (m, 5H), 7.72 (d,J=1.5 Hz, 1H), 7.79 (s, 1H), 8.11 (s, 1H), 8.85 (d, J=1.5 Hz, 1H). HPLCt_(R)=11.13 min (93.5%). MS: m/z362.1 [M+H]⁺.

TABLE 4 Compounds prepared according to Example 4 (Scheme 4) CompoundStructure MW ¹H NMR MS 1606

361.4 ¹H NMR (500 MHz, d₆- DMSO) δ 1.26 (d, J = 6.5 Hz, 6H), 3.13 (sept,J = 7.0 Hz, 1H), 5.75 (s, 2H), 7.31-7.41 (m, 5H), 7.96 (d, J = 7.5 Hz,1H), 8.21 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.70 (s, 1H) m/z 362.1 [M +H]⁺ 1615

361.4 ¹H NMR (500 MHz, d₆- DMSO) δ 0.92 (t, J = 7.5 Hz, 3H), 1.61 (sext,J = 7.5 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 5.75 (s, 2H), 7.37 (m, 4H),7.96 (d, J = 7.5 Hz, 1H), 8.24 (s, 1H), 8.52 (d, J = 7.5 Hz, 1H), 8.70(s, 1H). m/z 362.1 [M + H]⁺ 1616

361.4 ¹H NMR (500 MHz, CDCl₃) δ 1.00 (t, J = 7.5 Hz, 3H), 1.70 (sext, J= 7.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 5.61 (s, 2H), 7.39 (m, 5H),7.72 (d, J = 1.5 Hz, 1H), 7.79 (s, 1H), 8.11 (s, 1H), 8.85 (d, J = 1.5Hz, 1H) m/z 362.1 [M + H]⁺ 1617

339.4 ¹H NMR (500 MHz, CDCl₃): δ 1.01 (t, J = 7.5 Hz, 3H), 1.72 (sext, J= 7.5 Hz, 2H), 1.78-1.87 (m, 2H), 1.92-2.01 (m, 2H), 2.09-2.18 (m, 2H),2.29-2.39 (m, 2H), 2.66 (t, J = 7.5 Hz, 2H), 5.02 (quint, J = 7.0 Hz,1H), 7.76 (d, J = 1.5 Hz, 1H), m/z 340.1 [M + H]⁺ 7.90 (s, 1H), 8.13 (s,1H), 8.90 (d, J = 1.5 Hz, 1H); 1626

339.4 ¹H NMR (500 MHz, d₆- DMSO) δ 0.94 (t, J = 7.0 Hz, 3H), 1.62 (m,2H), 1.73 (m, 2H), 1.86 (m, 2H), 2.04 (m, 2H), 2.23 (m, 2H), 2.56 (t, J= 7.0 Hz, 3H), 5.15 (m, 1H), 8.01 (d, J = 7.5 Hz, 1H), 8.61 (d, J = 7.0Hz, 1H), 8.25 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 8.73 (s, 1H) m/z 340.1[M + H]⁺

Example 5

A range of 9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine carboxamides canbe prepared by condensation of 3-hydroxy-2-amino pyridinols 1-3 withdiethyl(ethoxymethylene) malonate to afford intermediate 5-1. Subsequentring closure in boiling acetic acid provides the ethyl ester 5-2.Hydrolysis with 2N NaOH gives acid 5-3, followed by conversion to acidchloride 5-4 is achieved using thionyl chloride. Target compounds 5-5are then synthesized by stirring acid chloride 5-4 with the appropriateamine (Scheme 5).

in whichR⁷ is H or methyl;R⁹ is H;R¹⁰ is C₃₋₈alkyl optionally interrupted with O, (CH₂)₁₋₂ 5 or 6 memberedN-containing heterocyclyl, (CH₂)₀₋₁ C₃₋₆cycloalkyl or CH₂ optionallysubstituted phenyl optionally fused with a 5 membered O containingheterocyclyl; orR⁹ and R¹⁰ together with the N to which they are attached form a 5 or 6membered ring.

Compound 1460 Diethyl 2-((3-hydroxypyridin-2-ylamino)methylene)malonate(5-1)

2-Amino-3-hydroxypyridine (1-3) (20.0 g, 0.18 mol) and diethyl2-(ethoxymethylene)malonate (55.0 mL, 0.27 mol) were stirred together ina flask at 130° C. for 40 min. The pyridine went into solution onheating after which a new yellow solid precipitated out of solution. Thereaction was cooled and the solid was recrystallised (EtOH) and airdried affording the product 5-1 as a yellow solid (39.0 g, 77%). ¹H NMR(d₆-DMSO, 500 MHz) δ1.20 (m, 6H), 4.17 (q, J=6.5 Hz, 2H), 4.22 (q, J=6.5Hz, 2H), 7.10 (t, J=7.0 Hz, 1H), 7.32 (d, J=7.0 Hz, 1H), 7.87 (d, J=2.1Hz, 1H), 9.13 (d, J=12.5 Hz, 1H), 10.88 (bs, 1H), 11.10 (d, J=12.5 Hz,1H).

Ethyl-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (5-2)

Diethyl-2-((3-hydroxypyridine-2-ylamin)methylene)malonate 5-1 (47.7 g,0.17 mol) was heated to reflux in acetic acid (400 mL) for 4.5 h. Thereaction was concentrated under reduced pressure to afford a yellowsolid. Recrystallisation (ethanol) gave the desired product 5-2 as apale yellow solid (30.6 g, 76%). ¹H NMR (d₆-DMSO, 500 MHz) δ1.30 (t,J=7.0 Hz 3H), 4.26 (q, J=7 Hz, 2H), 7.41 (t, J=8.5 Hz, 1H), 7.49 (d,J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.80 (s, 1H).

9-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (5-3)

The ester (5-2) (5.0 g, 0.02 mol) was suspended in ethanol (400 mL) towhich was added a 2N aqueous solution of sodium hydroxide (192 mL, 0.38mol). The reaction was heated at 40° C. for 3 h in which time a brightyellow precipitate was evident in the reaction mixture. The ethanol wasremoved under reduced pressure and the aqueous solution was extractedwith ethyl acetate (150 mL). The aqueous solution was acidified to pH 3using 10% aqueous HCl solution and left for 17 h in the fridge. Thereaction was filtered and the yellow solid was washed with water (20 mL)and dried under reduced pressure to give the title compound 5-3 as itsHCl salt (4.17 g, 86%). ¹H NMR (D₂O, 400 MHz) δ 2.74 (bs, 1H), 7.35 (brs, 2H), 8.61 (br s, 1H).

9-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonyl chloride (5-4)

9-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (5-3) (4.3g, 19.5 mmol) was heated to 80° C. in thionyl chloride for 2.5 h. Thevolatiles were removed in vacuo. Excess thionyl chloride was removed byazeotroping with toluene. The resulting9-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonyl chloride 5-4 wasisolated in quantitative yield as a beige solid.

N-cyclohexyl-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide(5-5) (1460)

9-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (5-3) (4.3g, 19.5 mmol) was heated to 80° C. in thionyl chloride for 2.5 h. Thevolatiles were removed in vacuo. Excess thionyl chloride was removed byazeotroping with toluene. The resulting acid chloride was isolated as abeige solid. The acid chloride (3.9 g, 17.4 mmol) was suspended inCH₂Cl₂ (65 mL) and cooled to 0°. DIEA (4.0 mL) and cyclohexylamine (4.5mL) were added and the reaction was stirred at rt for 2 days. Added 1MHCl until pH 3 followed by the addition of EtOH (65 mL). The suspensionwas filtered and the filtrate was concentrated to a volume of (10 mL).The solution was cooled and a green solid was collected by filtrationwashing with MeOH/H₂O (2:1) (×3) to afford the desiredN-cyclohexyl-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide5-4 (1.21 g, 24%). ¹H NMR (400 MHz, d6-DMSO) δ1.30 (m, 4H), 1.39 (m,1H), 1.39 (m, 2H), 1.87 (m, 1H), 3.86 (m, 1H), 7.48 (t, J=7.2 Hz, 1H),7.53 (d, J=7.2 Hz, 1H), 8.71 (d, J=6.8 Hz, 1H), 8.99 (s, 1H). MS: m/z288.1 [M+H]⁺.

TABLE 5 Compounds prepared according to Example 5 (Scheme 5) CompoundStructure MW ¹H NMR MS 1394

317.4 ¹H NMR (400 MHz, d6- DMSO) δ0.82 (m, 3H), 1.95 (m, 12H), 3.45 (m,2H), 1.79 (m, 2H), 7.24 (m, 1H), 7.33 (d, J = 6.8 Hz, 1H), 8.68 (d, J =6.8 Hz, 1H), 8.96 (br s, 1 H), 9.24 (s, 1H). m/z 316.2 [M − H]⁺ 1422

275.3 ¹H NMR (400 MHz, d6DMSO) δ0.82 (s, 3H), 1.22 (m, 4H), 1.50 (m,2H), 3.21 (m, 2H), 7.40 (s, 2H), 8.62 (s, 1H), 8.99 (s, 2H), 10.94 (brs, 1H). m/z 276.2 [M + H]⁺ 1423

247.3 ¹H NMR (400 MHz, d6DMSO) δ0.82 (m, 3H), 1.24 (q, J = 7.0 Hz, 2H),3.29 (t, J = 7.0 Hz, 2H), 3.22 (m, 2H), 4.51 (s, 2H), 7.37 (m, 2H), 8.97(s, 1H), 9.00 (m, 1H). m/z 248.1 [M + H]⁺ 1425

261.3 ¹H NMR (400 MHz, d6- DMSO) δ0.88 (s, 6H), 1.79 (m, 1H), 3.09 (m,2H), 7.40 (s, 1H), 8.63 (s, 1H), 8.99 (s, 1H), 9.02 (s, 1H), 10.95 (s,1H) m/z 262.1 [M + H]⁺ 1426

302.3 ¹H NMR (400 MHz, d6- DMSO) δ1.70 (m, 4H), 2.61 (m, 4H), 2.77 (m,2H), 3.51 (m, 2H), 7.20 (m, 2H), 8.38 (s, 1H), 8.82 (s, 1H), 9.02 (s,1H). m/z 303.2 [M + H]⁺ 1427

310.3 ¹H NMR (400 MHz, d6- DMSO) δ2.99 (m, 2H), 3.68 (m, 2H), 7.18 (t, J= 7.2 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 7.63 (m, 1H),8.40 (s, 1H), 8.60 (s, 1H), 8.97 (s, 1H), 9.05 (m, 1H) No mole- cularion observed 1428

259.3 ¹H NMR (400 MHz, CDCl₃) δ0.22 (m, 2H), 0.41 (m, 2H), 1.00 (m, 1H),3.21 (m, 2H), 7.21 (m, 2H), 8.61 (s, 1H), 9.00 (s, 1H), 9.19 (s, 1H).m/z 260.1 [M + H]⁺ 1429

329.7 ¹H NMR (400 MHz, d6- DMSO) δ4.55 (d, J = 6.0 Hz, 2H), 7.40 (m,4H), 7.52 (t, J = 7.61, 1H), 7.61 (d, J = 7.6 Hz, 1H), 8.73 (d, J = 6.8Hz, 1H), 8.95 (s, 1H), 9.38 (t, J = 6.0 Hz, 1H) m/z 330.1 [M + H]⁺ 1431

325.3 ¹H NMR (400 MHz, d6- DMSO) δ3.72 (s, 3H), 4.49 (d, J = 6.0 Hz,2H), 6.89 (d, J = 4.4 Hz, 2H), 7.27 (d, J = 4.4 Hz, 2H), 7.51 (t, J =7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 8.70 (d, J = 7.6 Hz, 2H), m/z330.1 [M + H]⁺ 8.98 (s, 1H), 9.27 (br s, 1H) 1432

339.3 ¹H NMR (400 MHz, d6- DMSO) δ4.46 (d, J = 5.6 Hz, 2H), 5.97 (s,2H), 6.83 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1 h), 6.92 (s, 1H),7.46 (m, 2H), 8.69 (d, J = 6.4 Hz, 1H), 9.02 (s, 1H), 9.33 (t, J = 5.6Hz, 1H) m/z 340.1 [M + H]⁺ 1433

223.2 ¹H NMR (400 MHz, d6- DMSO) δ1.15 (t, J = 7.2 Hz, 3H), 3.38 (q, J =7.2 Hz, 2H), 7.46 (m, 2H), 8.70 (m, 1H), 8.96 (t, J = 5.6 Hz, 1H), 9.00(s, 1H), 10.97 (br s, 1H) m/z 234.1 [M + H]⁺ 1436

273.3 ¹H NMR (400 MHz, d6- DMSO) δ1.47 (m, 2H), 1.59 (m, 2H), 1.69 (m,2H), 1.93 (m, 2H), 4.24 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.29 (t, J =7.2 Hz, 1H), 8.32 (d, J = 6.8 Hz, 1H), 8.88 (s, 1H), 9.13 (d, J = 7.6Hz, 1H) m/z 274.1 [M + H]⁺ 1437

331.3 ¹H NMR (400 MHz, d6- DMSO) δ4.53 (d, J = 5.6 Hz, 2H), 7.00 (t, J =7.2 Hz, 1H), 7.19 (m, 1H), 7.45 (m, 3H), 8.67 (d, J = 7.2 Hz, 1H), 8.91(m, 1H), 9.37 (br m, 1H) m/z 332.1 [M + H]⁺ 1440

289.3 ¹H NMR (400 MHz, d6- DMSO) δ0.84 (m, 3H), 1.25 (m, 6H), 1.52 (m,2H), 7.42 (m, 2H), 8.70 (m, 1H), 9.01 (m, 2H), 11.00 (br s, 1H) m/z290.1 [M + H]+ 1441

263.3 ¹H NMR (400 MHz, d6- DMSO) δ3.21 (s, 3H), 3.49 (m, 4H), 7.41 (m,2H), 8.65 (m, 1H), 9.01 (s, 1H), 9.17 (m, 1H). m/z 290.1 [M + H]⁺ 1445

219.2 ¹H NMR (400 MHz, d6- DMSO) δ2.87 (d, J = 4.4 Hz, 3H), 7.40 (m,2H), 8.69 (d, J = 5.6 Hz, 1H), 8.87 (d, J = 4.4 Hz, 1H), 8.99 (s, 1H),10.98 (br s, 1H) m/z 220.1 [M + H]⁺ 1446

296.3 ¹H NMR (400 MHz, d6- DMSO) δ4.59 (d, J = 6.0 Hz, 2H), 7.35 (m,1H), 7.45 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 8.45 (d, J = 4.4 Hz, 1H),8.58 (s, 1H), 8.70 (m, 1H), 9.01 (s, 1H), 8.47 (br t, J = 6.0 Hz, 1H).m/z 297.1 [M + H]⁺ 1447

296.3 ¹H NMR (400 MHz, d6- DMSO) δ4.89 (d, J = 6.0 Hz, 2H), 7.50 (t, J =7.2 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.80 (m, 2H), 8.35 (t, J = 7.1Hz, 1H), 8.76 (m, 2H). m/z 297.1 [M + H]⁺ 1450

296.3 ¹H NMR (400 MHz, d6- DMSO) δ4.81 (d, J = 4.8 Hz, 2H), 7.52 (m,2H), 7.89 (d, J = 5.2 Hz, 2H), 8.75 (d, J = 6.8 Hz, 1H), 8.80 (d, J =4.2 Hz, 2H), 8.98 (s, 1H), 9.66 (br s, 1H). m/z 297.1 [M + H]⁺ 1452

364.2 ¹H NMR (400 MHz, d6- DMSO) δ4.61 (d, J = 6.0 Hz, 2H), 7.41 (s,2H), 7.46 (m, 2H), 8.72 (d, J = 7.5 Hz, 1H), 9.00 (s, 1H), 9.49 (t, J =6.0 Hz, 1H) m/z 364.0 [M + H]⁺ 1453

363.3 ¹H NMR (400 MHz, d6- DMSO) δ4.64 (d, J = 6.0 Hz, 2H), 7.39 (m,2H), 7.58 (d, J = 4.0 Hz, 2H), 7.71 (d, J = 4.0 Hz, 2H), 8.68 (d, J =7.5 Hz, 1H), 9.00 (s, 1H), 9.43 (t, J = 6.0 Hz, 1H) m/z 364.1 [M + H]⁺1454

331.3 ¹H NMR (400 MHz, d6- DMSO) δ4.54 (d, J = 6.0 Hz, 2H), 7.20 (m,1H), 7.41 (m, 4H), 8.70 (d, J = 6.0 Hz, 1H), 9.01 (s, 1H), 9.45 (t, J =6.0 Hz, 1H). m/z 332.1 [M + H]⁺ 1461

301.4 ¹H NMR (400 MHz, d6- DMSO) δ0.96 (m, 2H), 1.11 (m, 3H), 1.42 (m,1H), 1.60 (m, 5H), 3.20 (t, J = 6.0 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H),7.53 (d, J = 7.2 Hz, 1H), 8.75 (d, J = 7.2 Hz, 1H), 8.99 (s, 1H), 9.02(t, J = 6.0 Hz, 1H). m/z 302.1 [M + H]+ 1462

305.4 ¹H NMR (400 MHz, d6- DMSO) δ0.85 (t, J = 4.2 Hz, 3H), 1.25 (m,8H), 1.53 (t, J = 6.0 Hz, 2H), 3.33 (m, 2H), 7.51 (t, J = 6.8 Hz, 1H),7.60 (d, J = 6.8 Hz, 1H), 8.73 (d, J = 6.8 Hz, 1H), 8.92 (t, m/z 306.2[M + H]⁺ J = 6.0 Hz, 1H), 8.94 (s, 1H) 1532

259.26 ¹H NMR (400 MHz, d6- DMSO) δ1.88 (m, 4H), 3.56 (m, 4H), 7.35 (bs,2H), 8.36 (bs, 1H), 8.57 (bs, 1H). m/z 260.2 [M + H]⁺ 1533

273.29 ¹H NMR (400 MHz, d6- DMSO) δ1.54 (m, 6H), 3.21 (m, 2H), 3.59 (m,2H), 7.12 (bs, 2H), 8.29 (bs, 1H), 8.51 (bs, 1H). m/z 274.3 [M + H]⁺1649

248.2 ¹H NMR (500 MHz, d₆- DMSO) δ1.29 (t, J = 7 Hz, 3H), 3.30 (s, 3H),4.26 (q, J = 7 Hz, 2H), 7.77 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz,1H), 8.82 (s, 1H), 8.98 (s, 1H). m/z 248.9 [M − H]⁺

Example 6

2-Methylamino substituted pyrimidones can be prepared according toScheme 6. Taking aniline 1-3 and heating with ethyl chloroacetoacetatein PPA following the procedure of Ferrarini, P. L II Farmaco 1995,50(1), p 69-72 generates after work-up the desired chloromethylderivative 6-1. Substitution of the chloro substituent with a variety ofamines generates the target amino compounds 6-2 (Scheme 6).

in which R⁵ is H or methyl;R⁶ is H or Cl;R⁹ and R¹⁰ are independently selected from H, C₁₋₈alkyl, CN, (CH₂)₀₋₂C₃₋₆ cycloalkyl, CH₂ optionally substituted phenyl or (CH₂)₀₋₃optionally substituted N containing 5 or 6 membered heterocyclyl; orR⁹ and R¹⁰ together with the N to which they are attached from anoptionally substituted 5 or 6 membered ring.

Compound 1408 2-(Chloromethyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one(6-1)

2-Amino-3-hydroxy pyridine (5.1 g, 46.3 mmol) was heated together withEthyl chloroacetoacetate (6.0 mL, 44.1 mmol) in polyphosphoric acid (60g) at 110° C. for 2 h. The reaction was cooled then ice was added. Then2N NaOH was carefully added until pH 4. The resulting beige precipitatewas collected by filtration and dried to afford the2-(chloromethyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one 6-1 (4.73 g,49%) as a light brown solid. ¹H NMR (400 MHz, d6-DMSO) δ4.62 (s, 2H),6.43 (s, 1H), 7.20 (m, 2H), 8.40 (d, J=6.8 Hz, 1H).

9-Hydroxy-2-((isobutylamino)methyl)-4H-pyrido[1,2-a]pyrimidin-4-oneHydrogen Chloride (6-2)

To 2-(chloromethyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (6-1) (206mg, 0.978 mmol) in anhydrous MeOH (5 mL) at 0° C. was addedisobutylamine (0.5 mL, 5.03 mmol). The mixture was then stirred at rtovernight. Solvent was removed in vacuo and EtOH (5 mL) and conc. HCl (1mL) were added. The product precipitated out and was collected byfiltration washing with cold ethanol. The resulting9-hydroxy-2-((isobutylamino)methyl)-4H-pyrido[1,2-a]pyrimidin-4-onehydrogen chloride 6-2 was isolated as a beige solid (82 mg, 30%). ¹H NMR(400 MHz, DMSO) 0.93 (t, J=7.0 Hz, 3H), 1.64 (m, 2H), 2.85 (m, 2H), 4.20(s, 2H), 6.39 (s, 1H), 7.22 (t, J=7.2 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H),8.42 (d, J=7.2 Hz, 1H), 9.03 (br s, 2H), 10.2 (br s, 1H). MS: m/z 248.1[M+H]⁺.

TABLE 6 Compounds prepared according to Example 6 (Scheme 6) CompoundStructure MW ¹H NMR MS 1400

219.24 ¹H NMR (400 MHz, DMSO) δ1.23 (t, J = 7.2 Hz, 1H), 2.99 (m, 2H),4.23 (s, 2H), 6.42 (s, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 7.2Hz, 1H), 9.21 (br s, 2H), 10.2 (s, 1H) m/z 220.1 [M + H]⁺ 1401

219.24 ¹H NMR (400 MHz, DMSO) δ2.78 (s, 3H), 2.79 (s, 3H), 4.39 (s, 2H),6.41 (s, 1H), 7.26 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 8.42(d, J = 7.2 Hz, 1H), 10.2 (s, 1H), 10.7 (s, 1H) m/z 220.1 [M + H]⁺ 1402

288.35 ¹H NMR (400 MHz, DMSO) δ1.24 (t, J = 7.0 Hz, 3H), 3.13 (m, 2H),3.33 (br m, 3H), 3.51 (br m, 5H), 4.02 (br s, 2H), 7.25 (t, J = 6.8 Hz,1H), 7.30 (d, J = 7.2 Hz, 1H), 8.47 (d, J = 6.8 Hz, 1H). m/z 289.2 [M +H]⁺ 1403

259.30 ¹H NMR (400 MHz, DMSO) δ1.43 (m, 2H), 1.75 (s, 2H), 2.01 (m, 2H),2.97 (m, 2H), 3.42 (m, 2H), 6.49 (s, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.33(d, J = 7.6 Hz, 1H), 8.45 (d, J = 7.6 Hz, 1H), 10.4 (br s, 1H), 10.6 (brs, 1H). m/z 260.1 [M + H]⁺ 1404

243.3 ¹H NMR (400 MHz, DMSO) δ2.45 (s, 2H), 2.92 (s, 3H), 3.13 (s, 1H),3.62 (s, 1H), 6.43 (s, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2Hz, 1H), 8.43 (d, J = 7.2 Hz, 1H). m/z 244.1 [M + H]⁺ 1405

247.3 ¹H NMR (400 MHz, DMSO) δ0.89 (t, J = 7.6 Hz, 3H), 1.33 (m, 2H),1.67 (m, 2H), 2.97 (m, 2H), 4.28 (s, 2H), 6.46 (s, 1H), 7.31 (t, J = 7.6Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 7.2 Hz, 1H), 9.21 (br s,2H), 10.2 (br s, 1H). m/z 248.1 [M + H]⁺ 1406

315.8 ¹H NMR (400 MHz, d6- DMSO) δ3.77 (s, 2H), 4.83 (s, 2H), 6.45 (s,1H), 7.18 (m, 2H), 7.37 (m, 4H), 8.38 (d, J = 7.2 Hz, 1H). m/z 316.1[M + H]⁺ 1407

233.3 ¹H NMR (400 MHz, DMSO) δ0.93 (t, J = 7.0 Hz, 3H), 1.64 (m, 2H),2.85 (m, 2H), 4.20 (s, 2H), 6.39 (s, 1H), 7.22 (t, J = 7.2 Hz, 1H), 7.31(d, J = 7.2 Hz, 1H), 8.42 (d, J = 7.2 Hz, 1H), 9.03 (br s, 2H), 10.2 (brs, 1H). m/z 220.1 [M + H]⁺ 1408

247.3 ¹H NMR (400 MHz, DMSO) δ0.95 (t, J = 7.0 Hz, 6H), 1.99 (m, 1H),2.89 (m, 2H), 4.21 (s, 2H), 6.42 (s, 1H), 7.24 (t, J = 7.0 Hz, 1H), 7.37(d, J = 7.2 Hz, 1H), 8.42 (d, J = 7.0 Hz, 1H), 9.18 (br s, 2H), 10.2 (brs, 1H). m/z 248.1 [M + H]⁺ 1409

299.3 ¹H NMR (400 MHz, DMSO) δ4.21 (br m, 4H), 6.39 (s, 1H), 7.24 (m,4H), 7.58 (m, 2H), 8.40 (d, J = 7.2 Hz, 1H), 9.75 (br s, 2H), 10.2 (brs, 1H), m/z 300.1 [M + H]⁺ 1410

303.4 ¹H NMR (400 MHz, DMSO) δ0.88 (t, J = 7.0 Hz, 2H), 1.19 (m, 10H),2.95 (b s, 2H), 4.21 (s, 2H), 6.40 (s, 1H), 7.23 (t, J = 7.0 Hz, 1H),7.35 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 7.0 Hz, m/z 304.2 [M + H]⁺ 1H),9.16 (br s, 2H), 10.2 (br s, 1H) 1411

245.3 ¹H NMR (400 MHz, DMSO) δ0.21 (m, 2H), 0.52 (m, 2H), 1.05 (m, 1H),2H), 2.90 (s, 2H), 4.21 (s, 2H), 6.39 (s, 1H), 7.21 (t, J = 7.0 Hz, 1H),7.32 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 7.0 Hz, 1H), 9.40 (br s, 2H),10.2 (br s, 1H). m/z 246.1 [M + H]⁺ 1412

318.4 ¹H NMR (400 MHz, D2O) δ2.11 (m, 2H), 3.11 (br m, 6H), 3.59 (br m,2H), 3.66 (br m, 2H) 3.92 (br m, 2H), 4.24 (s, 2H), 6.37 (s, 1H), 7.15(t, J = 7.6 Hz,1H), 7.24 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H).m/z 319.2 [M + H]⁺ 1413

261.3 ¹H NMR (400 MHz, d6 DMSO) δ0.93 (t, J = 7 Hz, 3H), 1.22 (m, 4H),1.61 (m, 2H), 2.97 (m, 2H), 4.21 (s, 2H), 6.41 (s, 1H), 7.23 (t, J = 7.0Hz, 1H), 7.28 (d, J = 7 Hz, 1H), 8.42 (d, J = 7 Hz, 1H), 9.00 (br s,2H). m/z 262.1 [M + H]⁺ 1414

282.3 ¹H NMR (400 MHz, d6 DMSO) δ4.23 (s, 2H), 4.38 (s, 2H), 6.40 (s,1H), (t, J = 7 Hz, 3H), 1.22 (m, 4H), 1.61 (m, 2H), 2.97 (m, 2H), 4.21(s, 2H), 6.41 (s, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 7.2 Hz,1H), 7.41 (d, J = 7.0 Hz, 1H), 7.82 (m, 1H), 8.43 (d, m/z 283.1 [M + H]⁺J = 7.2 Hz, 1H), 8.63 (s, 1H), 9.79 (br s, 2H). 1415

296.3 ¹H NMR (400 MHz, d6 DMSO) δ3.20 (t, J = 7.0 Hz, 2H), 3.39 (t, J =7.0 Hz, 2H), 4.25 (s, 2H), 6.40 (s, 1H), 7.22 (m, 4H), 7.66 (t, J = 7.2Hz, 1H), 8.42 (d, J = 7.2 Hz, 2H) m/z 297.2 [M + H]⁺ 1416

288.3 ¹H NMR (400 MHz, D20) δ2.13 (br s, 4H), 3.69 (m, 2H), 3.42 (m,4H), 3.75 (m, 2H), 4.51 (s, 2H), 6.58 (s, 1H), 7.36 (t, J = 7.2 Hz, 1H),7.45 (d, J = 7.2 Hz, 1H), 8.57 (d, J = 7.2 Hz, 1H). m/z 289.2 [M + H]⁺1417

288.3 ¹H NMR (400 MHz, D20) δ2.12 (m, 4H), 3.42 (m, 4H), 3.66 (m, 2H),3.76 (m, 2H), 4.51 (s, 2H), 6.58 (s, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.45(d, J = 7.2 Hz, 1H), 8.57 (d, J = 7.2 Hz, 1H). m/z 289.2 [M + H]⁺ 1418

304.3 ¹H NMR (400 MHz, D20) δ2.79 (m, 5H), 3.01 (m, 2H), 3.37 (m, 2H),3.80 (m, 4H), 4.37 (m, 2H), 6.57 (s, 1H), 7.34 (t, J = 7.2 Hz, 1H),7.40(d, J = 7.2 Hz, 1H), 8.44 (d, J = 7.2 Hz, 1H). m/z 305.2 [M + H]⁺1435

259.3 ¹H NMR (400 MHz, d6- DMSO) δ1.43 (m, 2H), 1.69 (m, 4H), 1.95 (m,2H), 3.48 (m, 1H), 4.21 (s, 2H), 6.41 (s, 1H), 7.25 (t, J = 7.2 Hz, 1H),7.37 (d, J = 7.2 Hz, 1H), 8.40 (d, J = 7.2 Hz, 1H), 9.38 (br s, 2H),10.21 (br s, 1H). m/z 260.3 [M + H]⁺ 1438

275.4 ¹H NMR (400 MHz, d4- MeOH) δ0.91 (s, 3H), 1.23 (m, 6H), 1.57 (m,2H), 2.61 (t, J = 7.2 Hz), 3.82 (s, 2H), 6.20 (s, 1H), 6.79 (s, 1H),7.02 (t, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H). m/z 276.3 [M + H]⁺1439

247.3 ¹H NMR (400 MHz, d4- MeOH) δ1.22 (t, J = 7.2 Hz, 6H), 3.02 (q, J =7.2 Hz, 4H), 4.14 (s, 2H), 6.34 (s, 1H), 7.00 (d, J = 6.8 Hz, 1H), 7.17(t, J = 6.8 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H). m/z 248.3 [M + H]⁺ 1442

281.3 ¹H NMR (400 MHz, d6- DMSO) δ4.19 (s, 2H), 6.38 (s, 1H), 7.22 (t, J= 7.2 Hz, 1H), 7.35 (m, 4H), 7.52 (m, 2H), 8.41 (d, J = 7.2 Hz, 1H),9.66 (br s, 2H), 10.15 (br s, 1H). m/z 282.1 [M + H]⁺ 1443

311.3 ¹H NMR (400 MHz, d6- DMSO) δ3.64 (s, 3H), 4.02 (s, 2H), 4.03 (s,2H), 6.35 (s, 1H), 6.83 (d, J = 4.8 Hz, 2H), 7.22 (d, J = 7.2 Hz, 1H),7.33 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 4.8 Hz, 2H), 8.40 (d, J = 7.2 Hz,1H), 9.74 (br s, 2H), 10.15 (br s, 1H) m/z 312.1 [M + H]⁺ 1444

303.3 ¹H NMR (400 MHz, d6- DMSO) δ4.23 (s, 2H), 6.06 (s, 1H), 6.20 (s,1H), 6.57 (t, J = 7.6 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.05 (d, J =7.2 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 8.40 (d, J = 7.2 Hz, 1H), 10.35(br s, 1H) m/z 304.4 [M + H]⁺ 1448

268.3 ¹H NMR (400 MHz, d6- DMSO) δ4.20 (s, 1H), 6.24 (s, 1H), 6.35 (brs, 1H), 6.51 (m, 3H), 7.02 (m, 2H), 7.14 (s, 1H), 7.19 (s, 1H), 8.39 (s,1H). m/z 267.1 [M − H]⁺ 1449

267.3 ¹H NMR (400 MHz, d6- DMSO) δ4.29 (s, 2H), 6.32 (s, 1H), 6.40 (brs, 1H), 6.55 (t, J = 7.5 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 7.07 (t, J =7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 8.43(d, J = 7.5 Hz, 1H). m/z 267.9 [M − H]⁺ 1451

285.3 ¹H NMR (400 MHz, d6- DMSO) δ4.20 (s, 2H), 6.23 (s, 1H), 6.56 (m,2H), 6.83 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.21 (d, J =7.5 Hz, 1H), 8.39 (s, 1H) m/z 285.9 [M + H]⁺ 1455

349.3 ¹H NMR (400 MHz, d6- DMSO) δ4.21 (s, 2H), 4.30 (s, 2H), 6.39 (s,1H), 7.21 (t, J = 6.8 Hz, 1H), 7.29 (d, J = 6.8 Hz, 1H), 7.76 (m, 4H),8.40 (d, J = 6.8 Hz, 1H), 9.95 (br s, 2H), 10.19 (s, 1H). m/z 350.1 [M +H]⁺ 1456

273.3 ¹H NMR (400 MHz, d6- DMSO) δ1.05 (m, 4H), 1.33 (m, 2H), 1.58 (m,1H), 1.73 (m, 2H), 2.02 (m, 2H), 3.00 (m, 1H), 4.22 (s, 2H), 6.43 (s,1H), 7.24 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 8.43 (s, 1H).m/z 274.1 [M + H]⁺ 1457

350.2 ¹H NMR (400 MHz, d6- DMSO) δ3.64 (s, 2H), 4.61 (s, 2H), 6.42 (s,2H), 7.19 (m, 2H), 7.38 (m, 1H), 7.55 (s, 1H), 7.58 (m, 1H), 8.41 (s,1H). m/z 351.1 [M + H]⁺ 1458

287.4 ¹H NMR (400 MHz, d6- DMSO) δ0.88 (m, 2H), 1.09 (m, 4H), 1.65 (m,6H), 2.89 (s, 2H), 4.20 (s, 2H), 6.41 (s, 1H), 7.22 (t, J = 6.8 Hz, 1H,7.29 (d, J = 6.8 Hz, 1H), 8.42 (d, J = 6.8 Hz, 1H), 9.16 (s, 2H), 10.18(s, 1H). m/z 288.2 [M + H]⁺ 1459

317.3 ¹H NMR (400 MHz, d6- DMSO) δ3.92 (s, 2H), 4.17 (d, J = 6.0 Hz,2H), 6.38 (s, 1H), 7.39 (m, 4H), 7.73 (t, J = 6.8 Hz, 1H), 8.41 (s, 1H),8.55 (br s, 2H), 10.02 (br s, 1H). m/z 318.1 [M + H]⁺ 1463

341.4 ¹H NMR (400 MHz, d6- DMSO) δ3.65 (s, 3H), 3.66 (s, 3H), 3.67 (s,2H), 4.60 (s, 2H), 6.38 (s, 1H), 6.81 (s, 2H), 6.96 (m, 2H), 7.09 (t, J= 7.2 Hz, 1H), 8.23 (d, J = 7.2 Hz, 1H). m/z 342.2 [M + H]⁺ 1464

365.3 ¹H NMR (400 MHz, d6- DMSO) δ4.00 (d, J = 6.0 Hz, 2H), 4.62 (s,2H), 6.44 (s, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H),7.35 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 8.37 (br s, 2H),8.43 (d, J = 7.2 Hz, 1H) m/z 366.1 [M + H]⁺ 1466

233.3 ¹H NMR (400 MHz, d6- DMSO) δ2.77 (s, 3H), 2.79 (s, 6H), 4.25 (s,2H), 6.80 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 9.60 (s, 1H),10.37 (br s, 1H). m/z 233.9 [M + H]⁺ 1467

313.3 ¹H NMR (500 MHz, d6- DMSO) δ2.77 (s, 3H), 3.65 (s, 2H), 4.58 (s,2H), 6.29 (s, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H),7.08 (m, 2H), 7.33 (m, 2H). No Mole- cular ion ob- served 1468

287.4 ¹H NMR (400 MHz, d6- DMSO) δ1.11 (m, 3H), 1.97 (m, 2H), 1.55 (m,1H), 1.63 (m, 2H), 2.01 (m, 2H), 2.81 (m, 3H), 2.99 (m, 1H), 4.14 (d, J= 6.0 Hz, 2H), 6.24 (s, 1H), 6.80 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 7.2Hz, 1H), 9.37 (br s, 2H), 9.71 (s, 1H). m/z 288.1 [M + H]⁺ 1469

329.8 ¹H NMR (400 MHz, d6- DMSO) δ2.79 (s, 3H), 3.62 (s, 2H), 4.77 (s,2H), 6.27 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H),7.33 (m, 4H). No Mole- cular ion ob- served 1470

247.3 ¹H NMR (400 MHz, d6- DMSO) δ0.91 (t, J = 7.2 Hz, 3H), 1.61 (m,2H), 2.79 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 6.22 (s, 1H), 6.80 (d, J =7.2 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H) m/z 248.1 [M + H]⁺ 1471

273.3 ¹H NMR (400 MHz, d6- DMSO) δ1.63 (m, 6H), 2.79 (s, 3H), 2.95 (m,2H), 3.23 (m, 2H), 4.22 (s, 2H), 6.23 (s, 1H), 6.80 (d, J = 6.8 Hz, 1H),7.03 (d, J = 6.8 Hz, 1H), 9.77 (s, 1H), 10.35 (br s, 1H) m/z 274.2 [M +H]⁺ 1476

310.4 ¹H NMR (400 MHz, d6- DMSO) δ2.82 (s, 3H), 3.50 (s, 4H), 4.55 (s,2H), 6.43 (s, 1H), 7.24 (m, 2H), 7.78 (t, J = 6.8 Hz, 1H), 7.89 (d, J =6.8 Hz, 1H), 8.35 (t, J = 6.8 Hz, 1 Hz), 8.42 (d, J = 6.8 Hz, 1H), 8.73(s, 1H). m/z 311.1 [M + H]⁺ 1478

311.4 ¹H NMR (400 MHz, d6- DMSO) δ2.20 (s, 3H), 3.68 (s, 2H), 4.59 (s,2H), 6.39 (s, 1H), 6.99 (d, J = 6.8 Hz, 1H), 7.10 (m, 4H), 7.19 (d, J =8.2 Hz, 2H), 8.22 (d, J = 6.8 Hz, 1H). No mole- cular ion ob- served1479

313.3 ¹H NMR (500 MHz, d6- DMSO) δ2.77 (s, 3H), 3.65 (s, 2H), 4.58 (s,2H), 6.29 (s, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H),7.08 (m, 2H), 7.33 (m, 2H) m/z 314.2 [M + H]⁺ 1485

261.3 ¹H NMR (400 MHz, d6- DMSO) δ0.92 (t, J = 7.2 Hz, 3H), 1.22 (m,2H), 1.65 (m, 2H), 2.79 (s, 3H), 4.39 (br m, 2H), 3.05 (m, 2H), 7.21 (t,J = 7.2 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 8.42 (s, 1H), 9.98 (br s,1H), 10.04 (s, 1H) m/z 262.1 [M + H]⁺ 1490

261.3 ¹H NMR (400 MHz, d6- DMSO) δ1.09 (t, J = 7.2 Hz, 6 Hz), 2.80 (s,3H), 3.11 (m, 4H), 4.24 (s, 2H), 6.21 (s, 1H), 6.79 (d, J = 6.8 Hz, 1H),7.03 (d, J = 6.8 Hz, 1H), 9.69 (s, 1H), 10.01 (br s, 1H) m/z 262.1 [M +H]⁺ 1491

257.3 ¹H NMR (400 MHz, d6- DMSO) δ2.79 (s, 3H), 3.90 (s, 1H), 4.16 (s,2H), 4.38 (s, 2H). 6.28 (s, 1H), 6.80 (d, J = 7.2 Hz, 1H), 7.01 (d, J =7.2 Hz, 1H), 9.59 (s, 1H), 11.02 (br s, 1H) m/z 258.1 [M + H]⁺ 1500

327.4 ¹H NMR (400 MHz, d6- DMSO) δ2.76 (s, 3H), 2.80 (s, 3H), 4.21 (s,2H), 4.38 (s, 2H), 6.81 (d, J = 6.8 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H),7.21 (m, 2H), 7.60 (m, 2H), 9.68 (s, 1H), 10.59 (s, 1H) m/z 328.5 [M +H]⁺ 1503

301.4 ¹H NMR (400 MHz, d6- DMSO) δ 0.85 (m, 2H), 1.11 (m, 4H), 1.61 (m,3H), 1.75 (m, 2H), 2.75 (m, 2H), 2.80 (s, 3H), 4.04 (s, 2H), 6.21 (s,1H), 6.80 (d, J = 6.8 Hz, 1H), 7.05 (d, J = 6.8 Hz, 1H), 9.18 (br s,2H), 9.60 (s, 1H) m/z 302.7 [M + H]⁺ 1504

310.4 ¹H NMR (400 MHz, d6- DMSO) δ 2.80 (s, 3H), 3.41 (m, 2H), 3.55 (m,2H), 4.22 (s, 2H), 6.25 (s, 1H), 6.80 (d, J = 6.8 Hz, 1H), 7.06 (d, J =6.8 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 8.37(d, J = 7.2 Hz, 1H), 8.77 (d, m/z 311.7 [M + H]⁺ J = 6.8 Hz, 1H), 9.66(br s, 1H). 1506

273.3 ¹H NMR (400 MHz, d6- DMSO) δ 0.87 (m, 3H), 1.62 (m, 5H), 3.01 (m,2H), 3.43 (m, 2H), 4.35 (s, 2H), 6.21 (s, 1H), 8.41 (s, 1H), 10.10 (brs, 1H), 10.29 (br s, 1H) m/z 274.3 [M + H]⁺ 1508

287.4 ¹H NMR (400 MHz, d6- DMSO) δ0.90 (s, 3H), 1.63 (m, 5H), 2.81 (s,3H), 2.95 (m, 2H), 3.39 (m, 2H), 4.21 (s, 2H), 6.23 (s, 1H), 6.80 (d, J= 6.8 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 9.76 (br s, 1H), 10.21 (br s,1H). m/z 288.4 [M + H]⁺ 1515

368.4 ¹H NMR (500 MHz, d6- DMSO) δ 3.71 (br m, 8H), 4.40 (s, 3H), 4.58(s, 2H), 6.51 (s, 1H), 7.37 (m, 3H), 7.55 (m, 1H), 7.77 (m, 1H), 8.48(d, J = 8.5 Hz, 1H), 10.28 (br s, 1H). m/z 369.4 [M + H]⁺ 1516

313.3 ¹H NMR (400 MHz, d6- DMSO) δ2.81 (s, 3H), 4.22 (s, 2H), 6.39 (s,1H), 7.25 (m, 4H), 7.42 (m, 1H), 7.71 (m, 1H), 8.43 (s, 1H), 10.2 (s,1H), 10.65 (br s, 1H) m/z 314.3 [M + H]⁺ 1517

313.3 ¹H NMR (400 MHz, d6- DMSO) δ 2.81 (s, 3H), 4.35 (s, 2H), 4.44 (s,2H), 6.38 (s, 1H), 7.23 (m, 3H), 7.39 (m, 2H), 7.57 (m, 1H), 8.43 (s,1H), 10.26 (br s, 1H), 10.83 (br s, 1H) m/z 314.3 [M + H]⁺ 1518

329.8 ¹H NMR (400 MHz, d6- DMSO) δ 2.80 (s, 3H), 4.37 (s, 2H), 4.43 (s,2H), 6.35 (s, 1H), 7.38 (m, 3H), 7.59 (s, 1H), 7.77 (s, 1H), 8.41 (s,1H), 10.25 (br s, 1H), 11.07 (br s, 1H) m/z 330.3 [M + H]⁺ 1519

348.8 ¹H NMR (400 MHz, d6- DMSO) δ2.83 (s, 3H), 4.22 (s, 2H), 4.35 (s,2H), 6.18 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H),7.41 (m, 2H), 7.55 (m, 1H), 7.67 (s, 1H), 9.65 (s, 1H), 10.60 (br s,1H). m/z 344.3 [M + H]⁺ 1521

287.4 ¹H NMR (400 MHz, d6- DMSO) δ1.12 (m, 1H), 1.20 (m, 2H), 1.51 (m,4H), 1.76 (m, 2H), 2.10 (m, 2H), 2.75 (s, 3H), 3.20 (m, 1H), 4.21 (m,1H), 4.56 (m, 1H), 6.43 (s, 1H), 7.24 (m, 2H), 8.41 (d, J = 6.8 Hz, 1H),10.35 (br s, 1H), 10.43 (br s, 1H). m/z 288.3 [M + H]⁺ 1522

382.4 ¹H NMR (400 MHz, d6- DMSO) δ 2.84 (s, 3H), 3.51 (m, 8H), 4.32 (brs, 2H), 4.41 (s, 2H), 6.27 (s, 1H), 6.84 (d, J = 6.8 Hz, 1H), 7.11 (d, J= 6.8 Hz, 1H) 7.28 (m, 2H), 7.46 (m, 1H), 7.68 (m, 1H), 9.79 (br s, 1H).m/z 383.4 [M + H]⁺ 1523

301.4 ¹H NMR (400 MHz, d6- DMSO) δ1.05 (m, 1H), 1.22 (m, 2H), 1.43 (m,2H), 1.51 (m, 1H), 1.76 (m, 2H), 2.09 (m, 2H), 2.66 (s, 3H), 2.81 (s,3H), 3.19 (m, 1H), 4.10 (m, 1H), 4.41 (m, 1H), 6.80 (d, J = 6.8 Hz, 1H),7.09 (d, J = 6.8 Hz, 1H), 9.79 (s, 1H), 10.08 (br s, m/z 302.4 [M + H]⁺1H). 1525

327.4 ¹H NMR (400 MHz, d6- DMSO) δ 2.81 (s, 3H), 2.84 (s, 3H), 4.25 (s,3H), 4.39 (s, 2H), 6.80 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H),7.21 (m, 1H), 7.40 (s, 1H), 7.50 (m, 1H), 9.75 (s, 1H), 10.80 (br s,1H). m/z 328.4 [M + H]⁺ 1527

327.4 ¹H NMR (400 MHz, d6- DMSO) δ 2.80 (s, 6H), 4.37 (s, 2H), 4.42 (s,2H), 6.20 (s, 1H), 6.80 (s, 1H), 7.07 (s, 1H), 7.21 (m, 2H), 7.41 (m,1H), 7.65 (m, 1H), 9.64 (s, 1H), 10.6 (br s, 1H). m/z 328.3 [M + H]⁺1531

296.1 ¹H NMR (400 MHz, d6- DMSO) δ 2.81 (s, 3H), 3.40 (s, 3H, obscuredby solvent), 4.60 (s, 2H), 6.19 (s, 1H), 6.75 (m, 1H), 6.83 (m, 1H),6.96 (m, 1H), 7.15 (m, 1H), 7.83 (m, 2H), 8.83 (s, 1H) m/z 297.3 [M +H]⁺ 1604

253.7 ¹H NMR (500 MHz, d6- DMSO) δ 2.30 (s, 3H), 2.48 (s, 3H), 3.52 (s,2H), 6.43 (s, 1H), 7.17 (s, 1H), 8.38 (s, 1H). m/z 254.0 [M + H]⁺ 1608

281.7 ¹H NMR (500 MHz, d6- DMSO) δ 1.14 (t, J = 7.5 Hz, 3H), 2.90 (q, J= 7.5 Hz, 2H), 4.63 (s, 2H), 6.34 (s, 1H), 6.45 (d, J = 2.5 Hz, 1H),7.86 (d, J = 2.5 Hz, 1H). m/z 282.1 [M + H]⁺ 1609

347.7 ¹H NMR (500 MHz, d6- DMSO) δ 2.38 (s, 3H), 3.87 (s, 2H), 4.64 (s,2H), 6.41 (s, 1H), 6.75 (s, 1H), 7.18 (app t, J = 9.0 Hz, 2H), 7.42 (m,2H), 8.05 (s, 1H m/z 348.1 [M + H]⁺ 1610

333.7 ¹H NMR (500 MHz, d6- DMSO) δ3.96 (s, 2H), 4.62 (s, 2H), 6.36 (s,1H), 6.54 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 7.0, 2.5 Hz, 2H), 7.45 (m,2H), 7.93 (d, J = 2.5 Hz, 1H). m/z 334.0 [M + H]⁺ 1612

384.6 ¹H NMR (500 MHz, d6- DMSO) δ 3.94 (s, 2H), 4.64 (s, 2H), 6.45 (s,1H), 6.82 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 9.5, 2.0 Hz, 1H), 7.19 (dd,J = 7.0, 2.5 Hz, 2H), 7.45 (m, 2H), 8.13 (d, J = 2.5 Hz, 1H). m/z 386.9[M + H]⁺ 1614

267.7 ¹H NMR (500 MHz, d6- DMSO) δ 1.05 (d, J = 7.5 Hz, 3H), 1.81 (q, J= 7.5 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 4.23 (s, 2H), 6.32 (s, 1H),8.80 (d, J = 2.5 1H), 8.17 (d, J = 2.5 Hz, 1H) m/z 268.1 [M + H]⁺ 1618

402.9 ¹H NMR (500 MHz, d6- DMSO) δ 3.52 (m, 4H), 4.19 (m, 2H), 4.43 (m,2H), 6.62 (s, 1H), 7.28 (app t, J = 9.5 Hz, 1H), 7.33 (app t, J = 8.0Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.65 (m, 1H), 7.62 (app t, J = 8.0Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H) m/z 403.1 [M + H]⁺ 1634

295.7 ¹H NMR (500 MHz, d6- DMSO) δ 3.35 (br m, 8H), 4.46 (s, 2H), 6.53(s, 1H), 7.42 (d, J = 2.5 Hz, 1H), 8.46 (d, J = 2.5 Hz, 1H), 10.78 (brs, 1H), 10.85 (br s, 1H). m/z 296.1 [M + H]⁺ 1635

279.7 ₁H NMR (500 MHz, d6- DMSO) δ 2.01 (d, J = 6.5 Hz, 4H), 3.07 (br s,2H), 3.59 (br s, 2H), 4.46 (s, 2H), 6.50 (s, 1H), 7.45 (d, J = 2.0 Hz,1H), 8.47 (d, J = 2.0 Hz, 1H), 10.73 (br s, 1H), 10.84 (br s, 1H). m/z280.1 [M + H]⁺ 1636

420.8 ¹H NMR (500 MHz, d6- DMSO) δ 3.49 (m, 4H), 4.15 (m, H), 4.47 (s,2H), 6.54 (s, 1H), 7.34 (m, 2H), 7.44 (s, 1H), 7.55 (s, 1H), 8.46 (s,1H), 10.70 (br s, 1H). m/z 421.1 [M + H]⁺ 1637

453.8 ¹H NMR (500 MHz, d6- DMSO) δ 2.68 (br s, 4H), 3.14 (br s, 4H),3.67 (s, 2H), 4.63 (s, 2H), 6.55 (s, 1H), 6.88 (s, 1H), 7.33 (d, J = 6.5Hz, 1H), 7.45 (m, 2H), 8.26 (s, 1H) m/z 453.1 [M + H]⁺ 1638

414.9 ¹H NMR (500 MHz, MeOD) δ 2.45 (m, 4H), 2.95 (m, 4H), 3.41 (s, 2H),3.62 (s, 3H), 4.64 (s, 2H), 6.37 (s, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.87(d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 2.0 Hz, 1H).m/z 415.2 [M + H]⁺ 1670

307.8 ¹H NMR (500 MHz, d6- DMSO) δ 0.932 (m, 4H), 1.59 (m, 2H), 1.79 (m,2H), 3.01 (m, 2H), 3.48 (m, 2H), 4.36 (s, 2H), 6.54 (s, 1H), 7.44 (s,1H), 8.47 (s, 1H) m/z 308.2 [M + H]⁺ 1699

398.9 ¹H NMR (400 MHz, d6- DMSO) δ 1.49 (m, 2H), 1.83 (m, 2H), 1.91 (m,2H), 2.75 (m, 2H), 2.91 (m, 1H), 3.40 (s, 2H), 4.60 (s, 2H), 6.28 (s,1H), 6.38 (d, J = 1.6 Hz, 1H), 7.23 (m, 5H), 7.80 (d, J = 1.6 Hz, 1H) Nomole- cular ion ob- served 1707

322.8 ¹H NMR (400 MHz, d6- CDCl₃) δ 1.12 (m, J = 7.6 Hz, 3H), 2.47 (q, J= 7.6 Hz, 2H), 2.49 (m, 4H), 2.66 (m, 4H), 3.58 (s, 2H), 6.61 (s, 1H),7.13 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H) m/z 323.1 [M + H]⁺

Example 7

7 and 8-Substituted alkynyl or ethyl pyrido-pyrimidinones 7-1 and 7-3can be prepared from ethynyl intermediate 4-3, shown in Scheme 7.Removal of the isopropoxy ether with conc. HBr or boron trichloridegenerates target compound 7-1. Alternatively 4-3 can undergo reductionby the action of sodium borohydride in the presence of Palladium onCarbon to generate ethyl derivative 7-2. Protective group removal as for4-3 yields target compound 7-3 (Scheme 7).

in which R³ is propyl.

Compound 16207-Ethynyl-9-hydroxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (7-1)

7-Ethynyl-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one 4-3 (150mg, 0.55 mmol) was dissolved in anhydrous CH₂Cl₂ and cooled to 0° C.Boron trichloride (0.85 mL, 0.85 mmol, 1.0M solution in CH₂Cl₂) wasadded dropwise to the solution. The reaction was allowed to warm to rtfor 3 h. The reaction was quenched with sat. aq. NaHCO₃ and the aqueouslayer was extracted with CH₂Cl₂ (×3). The combined organic layers werewashed with brine, dired over Na₂SO₄, filtered and concentrated to givea light yellow solid. The solid was dissolved in MeOH (10 mL) andconcentrated on a rotary evaporator. The process was repeated threetimes. The resulting residue was then recrystallized from hot ethanol toafford 7-ethynyl-9-hydroxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one 7-1as a white fluffy solid (32 mg, 25%). ¹H NMR (500 MHz, d6-DMSO) δ0.90(t, J=7.5 Hz, 3H), 1.59 (sext, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H),4.58 (s, 1H), 7.45 (s, 1H), 8.20 (s, 1H), 8.58 (d, J=1.5 Hz, 1H). HPLC:t_(R)=9.31 min (99%). MS: m/z 229.0 [M+H]*.

7-Ethyl-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (7-2)

7-Ethynyl-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one 4-3 (135mg, 0.5 mmol) was dissolved in isopropanol (5 MI) to which was thenadded AcOH (57 L, 1.0 mmol) and 10% Pd/C (14 mg). To the mixture wasadded NaBH₄ (76 mg, 2.0 mmol) with effervescence observed and thereaction was stirred for 30 minutes. A further 38 mg of NaBH₄ was addedand the reaction was allowed to stir for 30 minutes. The reaction wasthen quenched with 0.1M HCl until effervescence ceased. Sat. aq NaHCO₃was added until slightly basic and the mixture was then filtered througha pad of celite washing with CH₂Cl₂. The aqueous layer was extractedinto CH₂Cl₂ (×3). The combined extracts were dried over Na₂SO₄, filteredand concentrated to give the ethyl derivative 7-2 as light brown oil(130 mg, 95%). ¹H NMR (500 MHz, d6-DMSO) δ0.98 (t, J=7.5 Hz, 3H), 1.32(t, J=7.5 Hz, 3H), 1.52 (d, J=6.0 Hz, 6H), 1.69 (sext, J=7.5 Hz, 2H),2.63 (t, J=7.5 Hz, 2H), 2.71 (dq, J=7.5, 1.0 Hz, 2H), 4.76 (sept, J=6.0Hz, 1H), 6.83 (d, J=1.5 Hz, 1H), 8.25 (s, 1H), 8.52 (dt, J=1.5, 1.0 Hz,1H).

7-Ethyl-9-hydroxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (7-3) (1620)

7-Ethyl-9-isopropoxy-3-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (7-2) (128mg, 0.47 mmol) was dissolved in 48% HBr (3 mL) and then heated to refluxfor 1 h. After cooling the reaction was basified with sat. aq NaHCO₃ andthe aqueous layer was extracted into CH₂Cl₂ (×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to provide7-ethyl-9-hydroxy-3-propyl-4H-pyridio[1,2-a]pyrimidin-4-one 7-3 (101 mg,93%) as a light green powder. ¹H NMR (500 MHz, d6-DMSO) δ1.00 (t, J=7.5Hz, 3H), 1.31 (t, J=7.5 Hz, 3H), 1.70 (sext, J=7.5 Hz, 2H), 2.64 (t,J=7.5 Hz, 2H), 2.71 (q, J=7.5 Hz, 2H), 7.02 (d, J=1.5 Hz, 1H), 8.10 (s,1H), 8.40 (d, J=1.5 Hz, 1H). HPLC; t_(R)=8.80 min (98.1%). MS: m/z 233.0[M+H]*.

TABLE 7 Compounds prepared according to Example 7 (Scheme 7) CompoundStructure MW NMR MS 1613

232.3 ¹H NMR (500 MHz, d6-DMSO) δ0.90 (t, J = 7.5 Hz, 3H), 1.18 (t, J =7.5 Hz, 3H), 1.61 (m, 2H), 2.51 (m, 2H) 3.04 (t, J = 7.5 Hz, 2H), 7.19(d, J = 7.0 Hz, 1H0, 8.21 (s, 1H), 8.44 (d, J = 7.0 Hz, 1H) m/z 233.1[M + H]⁺ 1619

228.3 ¹H NMR (500 MHz, d6-DMSO) δ0.90 (t, J = 7.5 Hz, 3H), 1.59 (sext, J= 7.5 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 4.58 (s, 1H), 7.45 (s, 1H),8.20 (s, 1H), 8.58 (d, J = 1.5 Hz, 1H) m/z 229.1 [M + H]⁺ 1620

232.3 ¹H (500 MHz, CDCl₃) δ1.00 (t, J = 7.5 Hz, 3H), 1.31 (t, J = 7.5Hz, 3H), 1.70 (sext, J = 7.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.71 (q,J = 7.5 Hz, 2H), 7.02 (d, J = 1.5 Hz, 1H), m/z 233.09 [M + H]⁺ 8.10 (s,1H), 8.40 (d, J = 1.5 Hz, 1H) 1625

228.3 ¹H NMR (500 MHz, d6-DMSO) δ 0.92 (t, J = 7.0 Hz, 3H), 1.61 (m,2H), 2.52 (m, 2H), 1.86 (m, 2H), 4.79 (s, 1H), 7.17(d, J = 7.5 Hz, 1H),8.24(s, 1H), 8.34(d, J = 7. 5 Hz) m/z 229.1 [M + H]⁺

Example 8

8-Substituted aminomethyl carboxamide derivatives 8-1 can be preparedanalogously to those aminomethyl compounds 3-1 synthesized in Scheme 3.The carboxamide 5-1 is heated with a commercially available aminal toprovide target compounds 8-1 Scheme 8).

in which R⁹ and R¹⁰ are independently selected from C₅₋₆cycloalkyl, CH₂optionally substituted phenyl, C₁₋₄alkyl and phenyl fused with a 5membered O containing heterocyclyl.

Compound 1628N-cyclohexyl-8-((dimethylamino)methyl)-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide(8-1) (1628)

N-cyclohexyl-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide(181 mg, 0.63 mmol) was dissolved in toluene (6 mL) then heated withN,N,N,N-tetramethylmethylenediamine (500 μL, 3.67 mmol) at 85° C. for 3h. The resulting yellow precipitate was collected, after cooling, byfiltration. The crude product was washed with toluene to afford thecarboxamide 8-1 as yellow solid (173 mg, 80%). ¹H NMR (500 MHz, d6-DMSO)δ1.37 (m, 5H), 1.39 (m, 1H), 1.66 (m, 2H), 1.87 (m, 2H), 2.35 (s, 6H),3.72 (s, 2H), 3.86 (m, 1H), 7.45 (d, J=7.0 Hz, 1H), 8.61 (d, J=7.0 Hz,1H), 8.97 (s, 1H), 9.04 (d, J=8.0 Hz, 1H). HPLC: t_(R)=8.6 min (97.8%).MS: m/z 345.2 [M+H]⁺.

TABLE 8 Compounds prepared according to Example 8 (Scheme 8) CompoundStructure MW ¹H NMR MS 1628

344.4 ¹H NMR (500 MHz, d6- DMSO) δ1.37 (m, 5H), 1.39 (m, 1H), 1.66 (m,2H), 1.87 (m, 2H), 2.35 (s, 6H), 3.72 (s, 2H), 3.86 (m, 1H), 7.45 (d, J= 7.0 Hz, 1H), 8.61 (d, J = 7.0 Hz, 1H), 8.97 (s, 1H), 9.04 (d, J = 8.0Hz, 1H). m/z 345.2 [M + H]⁺ 1644

421.3 ¹H NMR (400 MHz, d6- DMSO) δ2.31 (s, 6H), 3.74 (s, 2H), 4.61 (d, J= 6.0 Hz, 2H), 7.41 (s, 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.63 (s, 1H),8.63 (d, J = 7.5 Hz, 1H), 8.97 (s, 1H), 9.50 (t, J = 6.0 Hz, 1H). m/z421.1 [M + H]⁺ 1658

318.4 ¹H NMR (400 MHz, d6-DMSO) δ0.93 (t, J = 7.6 Hz, 3H), 1.37 (sext, J= 7.6 Hz, 2H), 1.51 (quin, J = 7.6 Hz, 2H), 3.37 (ABq, J = 5.6 Hz, 2H),3.73 (s, 2H), 7.45 (d, J = 6.8 Hz, 1H), 8.61(d, J = 6.8 Hz, 1H), 8.97(s, m/z 319.1 [M + H]⁺ 1H), 9.02 (t, J = 5.6 Hz, 1 Hz). 1664

339.4 ¹H NMR (500 MHz, d6-DMSO) δ2.26 (s, 6H), 3.63 (s, 2H), 6.04 (s,2H), 6.99 (d, J = 8.5 Hz, 1H), 7.31 (m, 2H), 7.42 (s, 1H), 8.51 (s, 1H),8.57 (d, J = 1.5, 7.0 Hz, 1H) m/z 340.1 [M + H]⁺ 1669

330.4 ¹H NMR (500 MHz, d6- DMSO) δ 1.47 (m, 2H), 1.63 (m, 2H), 1.67 (m,2H), 1.91 (m, 2H), 2.30 (s, 6H), 3.72 (s, 2H), 4.25 (sext, J = 7.0 Hz,1H), 7.45 (d, J = 7.0 Hz, 1H), 8.59 (d, J = 7.0 Hz, 1H), 8.96 (s, 1H),9.03 (d, J = 7.5 Hz, 1H) m/z 331.1 [M + H]⁺ 1682

332.4 ¹H NMR (400 MHz, d6- DMSO) δ 0.87(t, J = 6.8 Hz, 3H), 1.32 (m,4H), 1.53 (t, J = 6.8 Hz, 2H), 2.23 (s, 6H), 3.33 (q, J = 6.4 Hz, 2H),3.71 (s, 2H), 7.45 (d, J = 6.8 Hz, 1H), 8.61 (d, J = 6.8 Hz, 1H), 8.97(s, 1H), 9.02 (t, J = 5.6 Hz, 1H). m/z 333.2 [M + H]⁺ 1710

291.3 ¹H NMR (500 MHz, CDCl₃) δ1.27 (t, J = 7.0 Hz, 3H), 2.45 (s, 6H),3.83 (s, 2H), 4.43(q, J = 7.0 Hz, 2H), 7.04 (d, J = 7.0 Hz, 1H), 8.79(d, J = 7.0 Hz, 1H), 9.05 (s, 1H). m/z 292.1 [M + H]⁺ 1712

370.4 ¹H NMR (400 MHz, CDCl₃) δ2.44(s, 6H), 3.83 (s, 2H), 4.65 (d, J =6.0 Hz, 2H), 7.02 (app t, J = 8.4 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1H),7.35 (m, 2H), 8.69 (d, J = 7.6 Hz, 1H), 9.36 (s, 1H), 3.93 (br t, J =6.0 Hz, 1H). m/z 371.2 [M + H]⁺

Example 9a

8 Substituted aryl and heteroaryl 3-carboxamide derivatives can beprepared according to Scheme 9a. Carboxamide 9-1 can be ortho iodinatedto give intermediate 9-2 which is then protected to afford compound 9-3.Suzuki coupling conditions are then employed to produce aryl orheteroaryl compounds 9-4. Finally, deprotection affords the targetcompounds 9-5.

in which R⁷ is optionally substituted 5 membered N-containingheterocyclyl or optionally substituted phenyl; R⁹ is butyl.

PB1657N-butyl-9-hydroxy-8-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide9-2

To a solution ofN-butyl-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (80 mg,0.31 mmol) in EtOH (5 mL) was added iodine (90 mg, 0.34 mmol) followedby 30% aqueous hydrogen peroxide (34 L). The reaction was allowed tostir at rt for 3 days at which timeN-butyl-9-hydroxy-8-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide9-2 had precipitated out of solution and was collected by filtration (71mg, 60% yield). ¹H NMR (400 MHz, d6-DMSO) δ0.91 (t, J=7.0 Hz, 3H), 1.35(m, 2H), 1.49 (m, 2H), 3.2 (m, 2H, obscured), 7.81 (d, J=8.0 Hz, 1H),8.40 (d, J=8.0 Hz, 1H), 8.96 (br s, 1H), 8.98 (s, 1H).

N-butyl-9-isopropoxy-8-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide9-3

N-butyl-9-hydroxy-8-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide9-2 (1.49 g, 38.5 mmol) was dissolved in DMF (50 mL) and treated withK₂CO₃ (2.12 g, 154 mmol) followed by 2-bromopropane (5 mL). The reactionwas heated to 50° C. for 17 h, cooled and concentrated to dryness. Theresidue was taken up in EtOAc and H₂O and the aqueous layer wasextracted into EtOAc (×2). The combined organic layers were washed withH₂O, brine, dried over Na₂SO₄, filtered and concentrated to provideN-butyl-9-isopropxy-8-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide9-3 (1.41 g, 85% yield). ¹H NMR (400 MHz, CDCl₃) 0.98 (t, J=7.6 Hz, 3H),1.44 (m, 9H), 1.62 (m, 2H), 3.49 (m, 2H), 5.44 (m, 1H), 7.63 (d, J=7.6Hz, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.95 (br s, 1H), 9.28 (s, 1H).

N-butyl-8-(3,5-dimethylisoxazol-4-yl)-9-isopropoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide(9-4)

A solution ofN-butyl-9-isopropoxy-8-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide9-3 (235 mg, 0.607 mmol), K₂CO₃ (1.21 mL, 2.42 mmol, 2M aqueoussolution), 3,5-dimethylisoxazole pinacol ester (176 mg, 0.789 mmol),Pd(PPh₃)₄ (59 mg, 0.051 mmol) in anhydrous DMF (10 mL) were degassedunder argon (×3) then heated to 100° C. for 4 h. After cooling, thereaction was diluted with H₂O (20 mL)/EtOAc (30 mL). The aqueous layerwas extracted into EtOAc (×2). The combined organic layers were washedwith H₂O, brine, dried over Na₂SO₄, filtered, concentrated and purifiedby flash chromatography eluting with 30 to 40% EtOAc/hexane to provideN-butyl-8-(3,5-dimethylisoxazol-4-yl)-9-isopropoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide9-4 (119 mg, 54%) as an off-white solid. ¹H NMR (400 MHz, d6-DMSO), 0.97(t, J=7.2 Hz, 3H), 1.21 (d, J=6.4 Hz, 6H), 1.44 (sext, J=7.2 Hz, 2H),1.66 (quin, J=7.2 Hz, 2H), (2.30 (s, 3H), 2.43 (s, 3H), (3.50 (q, J=7.2Hz, 6.0 Hz, 2H), 4.94 (sept, J=6.0 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 8.97(br t, J=6.0 Hz, 1H), 9.01 (d, J=7.2 Hz, 1H), 9.38 (s, 1H).

N-butyl-8-(3,5-dimethylisoxazol-4-yl)-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide(9-5) (PB1657)

N-butyl-8-(3,5-dimethylisoxazol-4-yl)-9-isopropoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide(9-4) (110 mg, 0.276 mmol) was heated to reflux in 48% aq HBr (3 mL) for2 h. The reaction was cooled then quenched with saturated aqueous NaHCO₃solution. The compound was extracted into CH₂Cl₂ (×3) and concentratedto afford N-butyl-8-(3,5-dimethylisoxazol-4-yl)-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide(9-5) (PB1657). ¹H NMR (400 MHz, CDCl₃) δ 0.93 (t, J=7.6 Hz, 3H), 1.37(sext, J=7.6 Hz, 2H), 1.51 (quin, J=7.6 Hz, 2H), 3.37 (q, J=6.8 Hz, 2H),7.49 (d, J=6.8 Hz, 1H), 8.69 (d, J=6.8 Hz, 1H), 8.90 (t, J=6.8 Hz, 1H),9.03 (s, 1H). Mass Spec: m/z 357.1187[M+H]⁺.

TABLE 9a Compounds prepared according to Example 9a (Scheme 9a) CompoundStructure MW NMR MS 1657

356.4 ¹H NMR (400 MHz, d6-DMSO) δ0.93 (t, J = 7.6 Hz, 3H), 1.37 (sext, J= 7.6 Hz, 2H), 1.51 (quin, J = 7.6 Hz, 2H), 3.37 (q, J = 6.8 Hz, 2H),7.49 (d, J = 6.8 Hz, 1H), 8.69 (d, J = 6.8 Hz, 1H), 8.90 (t, J = 6.8 Hz,1H), 9.03 (s, 1H). m/z 357.1 [M + H]⁺ 1660.1

355.4 ¹H NMR (400 MHz, d6-DMSO) δ 0.91 (t, J = 7.6 Hz, 3H), 1.36 (m,2H), 1.51 (m, 2H), 3.36 (m, 2H), 7.36 (m, 2H), 7.66 (d, J = 7.2 Hz, 1H),7.90 (m, 2H), 8.70 (d, J = 7.2 Hz, 1H), 8.99 (m, 1H), 9.02 (s, 1H). m/z356.1 [M + H]⁺ 1661

327.3 ¹H NMR (400 MHz, d6-DMSO) δ 0.91 (t, J = 7.0 Hz, 3H), 1.35 (m,2H), 1.51 (m, 2H), 3.35 (m, 2H), 7.27 (m, 2H), 7.85 (d, J = 7.5 Hz, 1H),7.89(t, J = 2.0 Hz, 1H), 8.51 (s, 1H), 8.68 (d, J = 7.5 Hz, 1H), 8.98(t, J = 6.0 Hz, 1H), 9.01 (s, 1H). m/z 328.2 [M + H]⁺

Example 9b

Compounds containing alkyl chains of three carbons or greater atposition 9 can be prepared according to Scheme 9b. Attempted Heckcoupling of compound 2-2 with vinyl acetic acid unexpectedly resulted inthe formation of decarboxylated product 9-1. Selective reduction of thealkene afforded compound 9-2. Removal of the isopropyl ether using HBrgenerated target compound 9-3

Compound 16059-Isopropoxy-3-isopropyl-8-(prop-1-enyl)-4H-pyrido[1,2-a]pyrimidin-4-one(9-1)

8-Iodo-9-isopropoxy-3-isopropyl-4H-pyrido[1,2-a]pyrimidin-4-one 2-2 (195mg, 0.524 mmol) was dissolved in anhydrous DMF (10 mL) and then degassedunder argon (×3). Triphenylphosphine (14 mg, 0.053 mmol), Pd(OAc)₂ (35mg, 0.0524 mmol) and vinyl acetic acid (1.0 mL, 11.5 mmol) were addedfollowed by another round of degassing. The reaction was then heated to100° C. for 4 h. The reaction was cooled and then partitioned betweenEtOAc/H₂O. The aqueous layer was extracted into EtOAc a further threetimes. Combined organic extracts were then dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography eluting with 10%EtOAc/petroleum ether 40-60° C. to afford the9-Isopropoxy-3-isopropyl-8-(prop-1-enyl)-4H-pyrido[1,2-a]pyrimidin-4-one9-1 as a yellow oil (147 mg, 85%). ¹H NMR (500 MHz, CDCl₃) δ1.30 (d,J=7.0 Hz, 1H), 1.36 (d, J=6.5 Hz, 1H), 2.01 (d, J=6.5 Hz, 3H), 3.24 (m,1H), 5.05 (sept, J=6.5 Hz, 1H), 6.49 (dq, J=16.0, 6.5 Hz, 1H), 6.90 (dd,J=16.0, 1.5 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 8.21 (s, 1H), 8.73 (d,J=7.5 Hz, 1H).

9-Isopropoxy-3-isopropyl-8-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (9-2)

9-Isopropoxy-3-isopropyl-8-(prop-1-enyl)-4H-pyrido[1,2-a]pyrimidin-4-one(9-1) (540 mg, 1.87 mmol) was dissolved in MeOH (20 MI), cooled to 0° C.then treated with 5 lots of sodium borohydride (500 mg, 13.5 mmol) over5 h. The reaction was left to stir for 2 days then concentrated. Theresidue was taken up in H₂O and CH₂Cl₂. The aqueous layer was thenextracted into CH₂Cl₂ (×3) and the organic layer was dried over Na₂SO₄,filtered and concentrated to provide the major product,9-Isopropoxy-3-isopropyl-8-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (9-2)as an oil (410 mg, 75%). ¹H NMR δ0.99 (t, J=7.0 Hz, 3H), 1.32 (d, J=6.5Hz, 6H), 1.35 (d, J=6.5 Hz, 6H), 1.66 (m, 2H), 2.74 (t, J=7.0 Hz, 2H),3.25 (sept, J=6.5 Hz, 1H), 5.13 (sept, J=6.5 Hz, 1H), 6.94 (d, J=7.5 Hz,1H), 8.22 (s, 1H), 8.77 (d, J=7.5 Hz, 1H).

9-hydroxy-3-isopropyl-8-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (9-3)(1605)

9-Isopropoxy-3-isopropyl-8-propyl-4H-pyrido[1,2-a]pyrimidin-4-one (9-2)(78 mg, 0.27 mmol) was heated to reflux in 48% aq HBr (2 mL) for 2 h.The reaction was cooled and concentrated and the resulting residue wasdiluted with H₂O. The mixture was then extracted into EtOAc (×3). Thecombined organic layers were washed with H₂O, dried over Na₂SO₄,filtered and concentrated to give a pale green solid. CH₃CN (5 mL) andH₂O (1 mL) were added to precipitate the target compound 9-3 as a flakeygreen solid (10 mg, 15%). ¹H NMR (500 MHz, d6-DMSO) δ0.91 (t, J=7.5 Hz,3H), 1.25 (d, J=6.5 Hz, 6H), 1.62 (sext, J=7.5 Hz, 2H), 2.66 (t, J=7.5Hz, 2H), 3.11 (sept, J=6.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 8.20 (s,1H), 8.44 (d, J=7.0 Hz, 1H). HPLC: t_(R)=9.72 (98.25%). MS: m/z 247.1[M+H]⁺.

Example 10

Compounds possessing 2-substituted alkyloxymethyl groups can be preparedaccording to Scheme 10. The chloromethyl intermediate 6-1 is heatedtogether with the appropriate alcohol in the presence of NaOH to formthe desired ether product 10-1 (Scheme 10).

2-(Ethoxymethyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (10-1)

The chloromethyl compound 6-1 (231 mg, 1.09 mmol) was dissolved in EtOH(17 mL) then treated with an aqueous solution of NaOH (5 mL, 6.25 mmol,1.25 M). The reaction was then heated to 70° C. o/n. The reaction wascooled and filtered to remove some insoluble material. The filtrate wasconcentrated to 7 mL and the resulting orange solution was extractedwith ether (15 mL). The aqueous layer was then acidified to pH 2 withconc. HCl (1 mL). The aqueous layer was then extracted into CH₂Cl₂ (×3)and the organic layers were dried over Na₂SO₄, filtered and concentratedto give an orange oil. Addition of 20% EtOAc/petroleum ether 40-60° C.(10 mL) afforded an off-white solid 10-1 that was collected byfiltration (45 mg, 19% yield). ¹H NMR (500 MHz, CDCl₃) δ1.21 (t, J=9.0Hz, 3H), 3.59 (q, J=9.0 Hz, 2H), 4.47 (s, 2H), 6.37 (s, 1H), 7.20 (m,2H), 8.46 (d, J=9.0 Hz, 1H). HPLC: t_(R)=6.21 min (98.3%). MS: m/z221.1[M+H]⁺.

TABLE 10 Compounds prepared according to Example 10 (Scheme 10) CompoundStructure MW ¹H NMR MS 1591

220.2 ¹H NMR (500 MHz, d6- DMSOδ1.21 (t, J = 9.0 Hz, 3H), 3.59 (q, J =9.0 Hz, 2H), 4.47 (s, 2H), 6.37 (s, 1H), 7.20(m, 2H), 8.46 (d, J = 9.0Hz, 1H). m/z 221.1 [M + H]⁺ 1646

234.3 ¹H NMR (500 MHz, CDCl₃) δ1.27 (d, J = 6.0 Hz, 6H), 3.76 (sept, J =6.0 Hz, 1H), 4.52 (s, 2H), 6.66 (s, 1H), 7.03 (t, J = 7.0 Hz, 1H), 7.15(d, J = 7.0 Hz, 1H), 8.53 (dd, J = 7.0, 1.5 Hz, 1H). m/z 235.1 [M + H]⁺1701

254.7 ¹H NMR (400 MHz, d6-DMSO) δ 1.30 (t, J = 7.0 Hz, 3H), 3.65 (q, J =7.0 Hz, 2H), 4.51 (s, 2H), 6.66 (s, 1H), 7.14 (d, J = 2.0 Hz, 1H), 8.58(d, J = 2.0 Hz, 1H) m/z 255.1 [M + H]⁺ 1705

240.6 ¹H NMR (400 MHz, d6- DMSO) δ3.51 (s, 3H), 4.46 (s, 2H), 6.61 (s,1H), 7.15 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H) m/z 241.1 [M +H]⁺

Example 11

Compounds containing alkoxymethyl group at position 3 can be preparedfrom the ester 5-2. Conversion of the phenol to a benzyl ether 11-1followed by DIBAL reduction gives alcohol 11-2. The alcohol is thenallowed to react with thionyl chloride to generate the intermediatealkyl chloride. Chloride displacement with an alcohol then givesalkoxymethyl compound 11-3. Ether cleavage provides the targetalkoxymethyl compound 11-4. Similarly compounds containing andalkylaminomethyl group at position 3 can be prepared in analogousfashion. Alcohol 11-2 is converted to the alkylaminomethyl compound 11-5via a chloride intermediate. Substitution with an amine generates thedesired alkylaminomethyl product 11-5. Removal of the protecting groupaffords the target compounds 11-6 (Scheme 11).

Compound 1424Ethyl-9-(benzyloxy)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate(11-1)

Ethyl-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (7.5 g,32.0 mmol) was dissolved in DMF (150 mL) then treated with K₂CO₃ (6.63g, 48 mmol), followed by benzyl bromide (8.0 mL, 67.3 mmol). Thereaction was stirred under N₂ for 3 days. To the reaction was added H₂O(50 mL) and the resulting tan solid was collected by filtration, washingwith H₂O (×3), then petrol (×3) to afford (7.78 g, 75%) ofethyl-9-(benzyloxy)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate(11-1) as a tan solid. ¹H NMR (400 MHz, d6-DMSO) δ1.28 (t, J=7.2 Hz,3H), 4.26 (q, J=7.2H, 2H), 5.31 (s, 2H), 7.43 (m, 5H), 7.50 (t, J=6.8Hz, 1H), 7.72 (d, J=6.8 Hz, 1H), 8.76 (d, J=6.8 Hz, 1H), 8.82 (s, 1H).

9-(Benzyloxy)-3-(hydromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (11-2)

Ethyl-9-(benzyloxy)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate(11-1) (1.54 g, 4.75 mmol) was dissolved in anhydrous 1:1CH₂Cl₂/anhydrous ether (60 mL) and cooled to −10° C. in an ice/saltbath. A solution of DIBAL-H (11.0 mL, 11 mmol, 1.0 M in hexanes) wasadded dropwise over 15 minute. The resulting bright yellow solution wasstirred under argon for 2 h. A further 1.0 mL of the above DIBAL-Hsolution was added and the reaction was left to warm to rt overnight.The reaction was cooled to 0° C. and quenched carefully with 10% K/Na⁺tartrate solution. Stirred at rt for 2 h then the suspension wasextracted into CH₂Cl₂ (×4). The combined organics were washed withbrine, dried over MgSO₄, filtered and concentrated to afford the alcohol11-2 as an oil (712 mg, 53%). ¹H NMR (400 MHz, d6-DMSO) δ4.44 (d, J=6.0Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.41 (m, 5H), 7.57 (d, J=7.2 Hz, 1H),8.36 (s, 1H), 8.58 (d, J=7.2 Hz, 1H).

9-(Benzyloxy)-3-methoxymethyl)-4H-pyrido[1,2-a]-4-one (11-3)

Alcohol 11-2 (317 mg, 1.13 mmol) was dissolved in anhydrous CH₂Cl₂ (7mL) and cooled to 0° C. Thionyl chloride (0.5 mL) was added dropwise andthe reaction was stirred for 1.5 h then concentrated to afford thechloride in quantitative yield. The crude chloride was suspended inanhydrous CH₂Cl₂ (10 mL) cooled to 0° C. then treated with a methanolicsolution of dimethylamine (1.5 mL, 3.0 mmol, 2.0 M). The reaction waswarmed to rt and stirred for 3 days. Volatiles were removed in vacuo andthe crude product was purified by flash chromatography eluting with 90%EtOAc/petroleum ether 40-60° C. to afford unreacted starting material.Further elution with 10% MeOH/CH₂Cl₂ provided methoxymethyl compound11-3 (115 mg, 34% yield) as yellow oil. ¹H NMR (400 MHz, d6-DMSO) δ3.21(s, 3H), 4.38 (s, 2H), 5.25 (s, 2H), 7.29 (t, J=7.2 Hz, 1H), 7.39 (m,5H), 7.56 (d, J=7.2 Hz, 1H), 8.30 (s, 1H), 8.49 (d, J=7.2 Hz, 1H).

9-Hydroxy-3-(methoxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (11-4)(1398)

9-(Benzyloxy)-3-methoxymethyl)-4H-pyrido[1,2-a]-4-one 11-3 (112 mg,0.362 mmol) in anhydrous CH₂Cl₂ (7 mL) was cooled to 0° C. then treatedwith boron tribromide (180 μL, 1.86 mmol). The reaction was warmed to rtand then stirred for 18 h. The reaction was cooled to 5° C. thenquenched cautiously with MeOH (15 mL). The reaction was stirred at rtfor 30 min then MeOH was removed in vacuo. The process was repeated (×3)and the compound was dried under high vacuum. The residue was thentreated with MeOH (1 mL) and ether (20 mL) to precipitate a brown powderafter sonication. The product was collected by filtration washing withether three times to afford the9-hydroxy-3-(methoxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one 11-4 as abrown solid (28 mg, 38%). ¹H NMR (400 MHz, d6-DMSO) δ3.29 (s, 3H), 4.36(s, 2H), 7.46 (t, J=7.2 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 8.22 (s, 1H),8.59 (d, J=7.2 Hz, 1H). HPLC: t_(R)=2.31 min (98.1%). MS: m/z 207.0[M+H]⁺.

9-Benzyloxy-3-((dimethylamino)methyl)-4H-pyrido[1,2-a]pyrimidin-4-one(11-5)

Alcohol 11-2 (317 mg, 1.13 mmol) was dissolved in anhydrous CH₂Cl₂ (7mL) and cooled to 0° C. Thionyl chloride (0.5 mL) was added dropwise andthe reaction was stirred for 1.5 h then concentrated to afford thechloride in quantitative yield. The chloride intermediate (344 mg, 1.14mmol) was dissolved in anhydrous CH₂Cl₂ (10 mL) and cooled to 0° C.Dimethylamine hydrogen chloride (512 mg, 6.28 mmol) was added followedby DIEA (1.10 mL, 6.28 mmol) and the resulting orange/red solution waswarmed to rt o/n. Volatiles were removed in vacuo then taken up inCH₂Cl₂ and sat. NaHCO₃. The aqueous layer was extracted into CH₂Cl₂ (×2)and the combined organic extracts were dried over Na₂SO₄, filtered,concentrated and purified by flash chromatography eluting with 5%MeOH/CH₂Cl₂. The product was then converted to the hydrogen chloridesalt. The residue was stirred in conc. HCl (2 mL) for 30 min thensolvent was removed under vacuum. A white solid was isolated and washedwith MeOH (2 mL)/ether (15 mL). Further washing with ether provided the9-benzyloxy-3-((dimethylamino)methyl)-4H-pyrido[1,2-a]pyrimidin-4-oneHCl salt 11-5 as a white powder (104 mg, 29%). ¹H NMR (400 MHz, d6-DMSO)δ2.77 (s, 3H), 2.79 (s, 3H), 4.25 (d, J=6.0 Hz, 2H), 5.36 (s, 2H), 7.42(m, 5H), 7.55 (d, J=6.8 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 7.66 (d, J=6.8Hz, 1H), 8.37 (s, 1H), 8.68 (d, J=6.8 Hz, 1H). 10.29 (br s, 1H).

3-((Dimethylamino)methyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-oneHydrogen Chloride (11-6) (1424)

9-Benzyloxy-3-((dimethylamino)methyl)-4H-pyrido[1,2-a]pyrimidin-4-oneHCl 11-5 was dissolved in MeOH (8 mL). Then 10% Pd on carbon (13 mg) wasadded under argon. The flask was evacuated three times then placed undera balloon of hydrogen. The reaction was stirred at rt for 4 h thenfiltered and concentrated to afford3-((dimethylamino)methyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-onehydrogen chloride 11-6 a pale yellow solid (30 mg, 37% yield). ¹H NMR(400 MHz, D₂O) 3.01 (s, 6H), 4.48 (s, 2H), 7.73 (t, J=6.8 Hz, 1H), 7.88(d, J=6.8 Hz, 1H), 8.84 (s, 1H), 8.84 (d, J=6.8 Hz, 1H). HPLC:t_(R)=1.74 min (100%). MS: m/z 220.1 [M+H]⁺.

Example 12

Compounds containing an S-methylene-dithiocarbamate group 12-2 can beprepared by reaction of intermediate 6-1 with carbon disulfide and anappropriately substituted amine in THE (Scheme 12).

in whichR⁶ is Cl;R⁹ and R¹⁰ are independently selected from H, C₁₋₂alkyl and CH₂pyridine; orR⁹ and R¹⁰ together with the N to which they are attached from anoptionally substituted 6 membered ring optionally containing N.

Compound 17137-Chloro-2-(chloromethyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one(12-2)

5-chloro-2-amino-pyridinol 12-1 (4.3 g, 29.7 mmol), 4-chloroacetoacetate(8.5 mL) were heated together in polyphosphoric acid (20 mL) at 110° C.for 2.5 h. The reaction mixture was cooled, crushed ice (30 g) was addedand the pH of the mixture was adjusted to 5, by the addition of 2N NaOH.A brown precipitate formed, that was collected by filtration, washingwith H₂O until the washings were colourless. The product was dried toafford the chloromethyl derivative as a brown powder (7.27 g, 100%). ¹HNMR (500 mHz, d6-DMSO) 4.67 (s, 2H), 6.59 (s, 1H), 7.27 (d, J=2.0 Hz,1H), 8.46 (d, J=2.0 Hz, 1H).

(7-Chloro-9-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methylmorpholine-4-dithiocarbamate (12-3) (1713)

7-Chloro-2-(chloromethyl)-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one(12-1) (235 mg, 0.96 mmol) was dissolved in THE (4 mL), then carbondisulfide (65 μL) was added at 0° C., followed by the addition ofmorpholine (175 μL). The reaction was stirred at 0° C. for 30 min thenallowed to warm to rt over 18 h. The reaction was quenched by theaddition of H₂O (2 mL). After stirring for 2 h at rt, a beigeprecipitate resulted that was collected by filtration. ¹H NMR (400 MHz,d6-DMSO) δ 3.67 (m, 4H), 3.97 (m, 2H), 4.23 (m, 2H), 4.59 (s, 2H), 6.50(s, 1H), 7.23 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H). MS (ESI+ve):m/z 371.9 [M+H]⁺.

TABLE 11 Compounds prepared according to Example 12 (Scheme 12) CompoundStructure MW Proton NMR MS 1714

357.9 ¹H NMR (500 MHz, d6-DMSO) δ1.18 (m, 6H), 3.76 (q, J = 7.5 Hz, 2H),3.96 (q, J = 7.5 Hz, 2H), 6.27 (s, 1H), 6.78 (d, J = 2.0 Hz, 1H), 7.87(d, J = 2.0 Hz, 1H) m/z 358.0 [M + H]⁺ 1720

383.9 ¹H NMR (400 MHz, d6-DMSO) δ0.91 (m, 5H), 1.11 (m, 3H), 1.21 (m,2H), 1.60 (m, 1H), 1.78 (m, 4H), 2.80 (m, 2H), 3.19 (m, 2H), 4.42 (br s,1H), 4.59 (d, J = 5.6 Hz, 1H), 5.24 (br s, 1H), 6.51 m/z 384.1 [M + H]⁺(s, 1H), 7.29 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H). 1721

392.9 ¹H NMR (400 MHz, d6-DMSO) δ 4.52 (s, 2H), 5.16 (d, J = 7.6 Hz,2H), 6.52 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.98 (m, 2H), 8.36 (t, J =7.2 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.79 d, J = 5.2 Hz, 1H), 11.67(s, 1H) m/z 393.025 [M + H]⁺

Example 13

Acyl hydrazine and acyl hydrazide derivatives can be prepared from anester intermediate 11-1 (Scheme 11) by heating with an aqueous solutionof hydrazine hydrate in Ethanol to generate compound 13-1. Hydrazine13-1 is allowed to react with commercially available aldehydes toprovide hydrazide 13-2 (Scheme 13).

in whichR⁹ is optionally substituted imidazolyl.

Compound 17119-(Benzyloxy)-4-oxo-4H-pyrido[1,2-a]pyrimidinine-3-carbohydrazide (13-1)(1711)

To a solution of Ethyl9-(benzyloxy)-4-oxo-4H-[1,2-a]pyrimidine-3-carboxylate (11-1) (493 mg,1.59 mmol), was added hydrazine hydrate (2 mL) and three drops of conc.H₂SO₄. The reaction was heated to reflux for 3 h, then cooled. Thehydrazide precipitated out of solution as a fluffy white solid and wascollected by filtration (388 mg, 83%). ¹H NMR (400 MHz, d6-DMSO) δ4.63(br s, 2H), 5.33 (s, 2H), 7.42 (m, 6H), 7.70 (d, J=8.0 Hz, 1H), 8.79 (d,J=8.0 Hz, 1H), 8.97 (s, 1H), 9.76 (br s, 1H). MS (ES+ve): m/z 311.11[M+H]⁺.

Compound 17239-Benzyloxy-N″-2-(hydroxybenzilidene)-4-oxo-4-H-pyrido[1,2-a]pyrimidine-3-carbohydrazide(13-2)(1723)

9-(Benzyloxy)-4-oxo-4H-pyrido[1,2-a]pyrimidinine-3-carbohydrazide (13-1)(80 mg, 0.258 mmol), salicylaldehyde (50 mg, 0.41 mmol) were heated toreflux in EtOH (12 mL) for 4 h. A cream precipitate resulted. Afterallowing the reaction mixture to cool, the resulting9-Benzyloxy-N″-2-(hydroxybenzilidene)-4-oxo-4-H-pyrido[1,2-a]pyrimidine-3-carbohydrazide(13-2) (80 mg, 75%) was collected by filtration. ¹H NMR (400 MHz,d6-DMSO) δ5.32 (s, 2H), 6.89 (m, 2H), 7.27 (t, J=8.0 Hz, 1H), 7.37 (m,4H), 7.52 (m, 3H), 7.74 (d, J=8.0 Hz, 1H), 8.68 (s, 1H), 8.80 (d, J=7.2Hz, 1H), 9.03 (s, 1H), 11.25 (br s, 1H), 12.1 (br s, 1H). MS (ESI+ve):m/z 415.2 [M+H]⁺.

TABLE 12 Compounds prepared according to Example 13 (Scheme 13) CompoundStructure MW Proton NMR MS 1723

414.41 ¹H NMR (400 MHz, d6- DMSO) δ 5.32 (s, 2H), 6.89 (m, 2H), 7.27 (t,J = 8.0 Hz, 1H), 7.37 (m, 4H), 7.52 (m, 3H), 7.74 (d, J = 8.0 Hz, 1H),8.68 (s, 1H), 8.80 (d, J = 7.2 Hz, 1H), 9.03 (s, 1H), 11.25 (br s, 1H),12.1 (br s, 1H). m/z 415.2 [M + H]⁺ 1724

402.41 ¹H NMR (400 MHz, d6- DMSO) δ 3.96 (s, 3H), 5.36 (s, 2H), 7.40 (m,4H), 7.52 (m, 4H), 7.78 (d, J = 6.8 Hz, 1H), 8.63 (s, 1H), 8.83 (d, J =6.8 Hz, 1H), 9.05 (s, 1H), 12.3 (s, 1H), m/z 403.2 [M + H]⁺ 1732

428.44 ¹H NMR (400 MHz, d6- DMSO-did not fully dissolve) δ 3.77 (s, 3H),5.32 (s, 2H), 7.01 (m, 1H), 7.08 (m, 1H), 7.28 (m, 2H), 7.37 (m, 1H),7.41 (m, 2H), 7.50 (m, 2H), 7.77 (d, J = 7.2 Hz, 1H), 8.42 (s, 1H), 8.65(s, 1H), 8.82 (m, 1H), 9.03 (s, 1H), 12.05 (s, 1H) m/z 429.2 [M + H]⁺

Example 14

2-Methyl substituted pyridopyrimidine derivatives can be synthesized byreaction of 2-amino-3-pyridinols 14-1 with commercially available ethyl(acetoacetates) 14-2 to generate the 2-substituted pyridopyrimidine ringsystem 14-3. Regioselective iodination to provide 14-4 was achieved bythe action of iodine and hydrogen peroxide. A Suzuki coupling reactioncan be carried out with Pd(PPh₃)₄ as catalyst and commercially availableboronic acids R⁷B(OH)₂ or boronate esters R⁷B(OR⁵)₂ to afford aryl andheteroaryl compounds 14-5 (Scheme 14).

in which R³ is C₁₋₄alkyl or benzyl;R⁶ is H or Cl; andR⁷ is H, I, pyridinyl optionally substituted pyrazolyl or optionallysubstituted isoxazolyl.

3-butyl-7-chloro-9-hydroxy-2-methyl-4H[1,2-a]pyrimidin-4-one (14-3)(1667)

2-amino-5-chloropyridinol (2.0 g, 14 mmol), ethyl-2-butylacetoacetate(3.87 g, 20 mmol) and polyphosphoric acid (25 g) were heated together at110° C. for 4 hours. After cooling, H₂O was added and the pH taken to 4with 2N NaOH. The resulting yellow precipitate was collected byfiltration, washed with H₂O then ether and dried to afford3-butyl-7-chloro-9-hydroxy-2-methyl-4H[1,2-a]pyrimidin-4-one PB1667(2.54 g, 69%) as a yellow powder. ¹H NMR (500 MHz, d6-DMSO) δ 0.94 (t,J=7.5 Hz, 2H), 1.42 (m, 2H), 1.52 (m, 2H), 2.48 (s, 3H), 2.67 (t, J=7.4Hz, 2H), 7.01 (s, 1H), 8.48 (s, 1H). MS: m/z 267.11[M+H]⁺.

3-butyl-7-chloro-9-hydroxy-8-iodo-2-methyl-4H[1,2-a]pyrimidin-4-one(14-4) (1688)

To a solution of3-butyl-7-chloro-9-hydroxy-2-methyl-4H[1,2-a]pyrimidin-4-one (14-3) (900mg, 3.4 mmol) in EtOH (35 mL) was added iodine (940 mg, 3.7 mmol),followed by the dropwise addition of 30% aqueous hydrogen peroxide (380ML). The reaction was stirred o/n at rt and the resulting precipitatewas filtered off, washing with EtOH (3×5 mL) to provide the3-butyl-7-chloro-9-hydroxy-8-iodo-2-methyl-4H[1,2-a]pyrimidin-4-one(14-4) PB1688 as yellow powder (955 mg, 72% yield). ¹H NMR (500 MHz,d6-DMSO) δ 0.90 (t, J=7.0 Hz, 3H), 1.33 (m, 2H), 1.43 (m, 2H), 2.53 (s,3H), 2.55 (s, 2H), 8.31 (s, 1H).

3-butyl-7-chloro-9-isopropoxy-8-iodo-2-methyl-4H[1,2-a]pyrimidin-4-one(14-5) (1689)

To a stirred solution of3-butyl-7-chloro-9-hydroxy-8-iodo-2-methyl-4H[1,2-a]pyrimidin-4-one 14-4(955 mg, 2.40 mmol) in DMF (12 mL) was added K₂CO₃ (1.35 g, 9.7 mmol),followed by 2-bromopropane (700 μL, 7.5 mmol) and the reaction wasstirred at 50° C. for 6 days. The reaction was diluted with H₂O andEtOAc and the aqueous layer was further extracted into EtOAc (×2). Theresulting organic layers were washed with H₂O, brine, dried over Na₂SO₄,filtered and concentrated to give3-butyl-7-chloro-9-isopropoxy-8-iodo-2-methyl-4H[1,2-a]pyrimidin-4-one(14-5) 1689 as a yellow solid (611 mg, 59% yield). ¹H NMR (500 MHz,d6-DMSO) δ0.97 (t, J=7.0 Hz, 3H), 2.38 (m, 8H), 1.42 (m, 2H), 2.41 (s,3H), 2.58 (m, 2H), 5.39 (m, 1H), 8.67 (s, 1H). MS: m/z 435.0 [M+H]⁺.

3-butyl-7-chloro-9-isopropoxy-2-methyl(pyridin-4-yl)-4H[1,2-a]pyrimidin-4-one(14-6)

3-butyl-7-chloro-9-isopropoxy-8-iodo-2-methyl-4H[1,2-a]pyrimidin-4-one14-5 (300 mg, 0.69 mmol) was dissolved in DMF (15 mL) and 2M K₂CO₃ (1.4mL) in a Schlenk flask. The solution was degassed and back-filled withargon (×2). Then 4-pyridinyl boronic acid (130 mg, 1.03 mmol) andPd(PPh₃)₄ (55 mg, 7 mol %) were added to the reaction at which time theflask was degassed a further 5 times. The reaction flask was heated to95° C. o/n. After cooling, volatiles were removed under reducedpressure. The residue was then diluted with H₂O (20 mL) and extractedinto EtOAc (3×10 mL). The combined organic layers were washed with H₂O(2×10 mL), dried Na₂SO₄, filtered and concentrated to afford crude3-butyl-7-chloro-9-isopropoxy-2-methyl(pyridin-4-yl)-4H[1,2-a]pyrimidin-4-one(14-6) as a brown oil (284 mg). Compound was taken onto the next stepwithout purification.

3-butyl-7-chloro-9-hydroxy-2-methyl(pyridin-4-yI)-4H-[1,2-a]pyrimidin-4-one(14-7) (1690)

3-butyl-7-chloro-9-isopropoxy-2-methyl(pyridin-4-yl)-4H[12-a]pyrimidin-4-one(14-6) (284 mg, 0.74 mmol) was dissolved in anhydrous CH₂Cl₂ (5 mL)cooled to −10° C. then a 1.0M solution of boron trichloride in CH₂Cl₂(5.2 mL, 5.2 mmol) was added. After stirring for 5 min the reaction waswarmed to rt o/n. Methanol was cautiously added to the reaction whichwas then concentrated in vacuo. This procedure was repeated five timesthen the residue was sonicated with EtOH only, producing3-butyl-7-chloro-9-hydroxy-2-methyl(pyridin-4-yl)-4H[1,2-a]pyrimidin-4-one(14-7) PB1690 as a cream coloured solid that was collected by filtration(116 mg, 46% yield). ¹H NMR (500 MHz, d6-DMSO) δ80.91 (t, J=7.0 Hz, 3H),1.35 (m, 2H), 1.47 (m, 2H), 2.58 (s, 3H), 2.60 (m, 2H), 8.17 (s, 1H),8.23 (s, 1H), 9.34 (br s, 1H). MS: m/z 344.1 [M+H]⁺.

TABLE 13 Compounds prepared according to Example 14 (Scheme 14) CompoundStructure MW Proton NMR Mass Spec 1662

238.7 ¹H NMR (400 MHz, d6- DMSO) δ1.10 (t, J = 7.0 Hz, 3H), 2.52 (s,3H), 2.63 (q, J = 7.0 Hz, 2H), 7.15 (s, 1H), 8.41 (s, 1H) m/z 239.1 [M +H]⁺ 1663

224.6 ¹H NMR (500 MHz, d6- DMSO) δ 2.11 (s, 3H), 2.42 (s, 3H), 7.09 (d,J = 2.0 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H) m/z 225.0 [M + H]⁺ 1665

350.5 ¹H NMR (500 MHz, d6- DMSO) δ 2.08 (s, 3H), 2.44 (s, 3H), 8.19 (s,1H). m/z 350.9 [M + H]⁺ 1666

339.4 ¹H NMR (400 MHz, d6- DMSO) δ1.06 (t, J = 7.2 Hz, 3H), 2.48 (s,3H), 2.57 (q, J = 7.2 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 8.10 (d, J =7.6 Hz, 1H) m/z 331.1 [M + H]⁺ 1667

266.7 ¹H NMR (500 MHz, d6- DMSO) δ0.94 (t, J = 7.5 Hz, 2H), 1.42 (m,2H), 1.52 (m, 2H), 2.48 (s, 3H), 2.67 (t, J = 7.4 Hz, 2H), 7.01 (s, 1H),8.48 (s, 1H) m/z 267.1 [M + H]⁺ 1672

300.7 ¹H NMR (500 MHz, d6- DMSO) δ2.42 (s, 3H), 3.98 (s, 2H), 7.16 (m,2H), 7.23 (m, 4H), 8.42 (s, 1H) m/z 301.1 [M + H]⁺ 1673

319.7 ¹H NMR (500 MHz, d6- DMSO) δ2.11 (s, 3H), 2.14 (s, 2H), 2.29 (s,3H), 2.50 (s, 3H), 8.49 (s, 1H) m/z 320.1 [M + H]⁺ 1687

280.8 ¹H NMR (500 MHz, d6- DMSO) δ1.05 (t, J = 7.5 Hz, 3H), 1.34 (s,3H), 1.35 (s, 3H), 2.41 (s, 3H), 2.61 (q, J = 7.5 Hz, 2H), 4.87 (sept, J= 6.0 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H) m/z281.1 [M + H]⁺ 1688

392.6 ¹H NMR (500 MHz, d6- DMSO) δ0.90 (t, J = 7.0 Hz, 3H), 1.33 (m,2H), 1.43 (m, 2H), 2.53 (s, 3H), 2.55 (s, 2H), 8.31 (s, 1H) m/z 393.0[M + H]⁺ 1689

434.7 ¹H NMR (500 MHz, d6- DMSO) δ0.97 (t, J = 7.0 Hz, 3H), 2.38 (m,8H), 1.42 (m, 2H), 2.41 (s, 3H), 2.58 (m, 2H), 5.39 (m, 1H), 8.67 (s,1H) m/z 435.0 [M + H]⁺ 1690

343.8 ¹H NMR (500 MHz, d6- DMSO) δ0.91 (t, J = 7.0 Hz, 3H), 1.35 (m,2H), 1.47 (m, 2H), 2.58 (s, 3H), 2.60 (m, 2H), 8.17 (s, 1H), 8.23 (s,1H), 9.34 (br s, 1H) m/z 344.1 [M + H]⁺ 1694

388.89 ¹H NMR (500 MHz, d6- DMSO) δ0.85 (s, 3H), 0.87 (s, 3H), 0.92 (t,J = 7.0 Hz, 3H), 1.35 (m, 2H), 1.44 (m, 2H), 2.14 (m, 1H), 2.58 (s, 3H),4.00 (d, J = 7.0 Hz, 2H), 7.97 (s, 1H), 8.26 (s, 1H), 8.43 (s, 1H) m/z389.3 [M + H]⁺ 1698

210.62 ¹H NMR (400 MHz, d6- DMSO) δ2.47 (s, 3H), 6.52 (s, 1H), 7.78 (d,J = 1.6 Hz, 1H), 8.60 (d, J = 1.6 Hz, 1H) m/z 211.0 [M + H]⁺

Example 15

7-Substituted sulphonamides can be prepared from pyridopyrimidines 15-1.A regioselective nitration ortho to the phenol followed by reduction tothe aniline 15-3 is achieved with sodium dithionite. Reaction of theaniline with sulfonyl chloride generates the target sulphonamide 15-4.

Compound 17179-Hydroxy-3-isopropyl-8-nitro-4H-pyrido[1,2-a]pyrimidin-4-one (15-2)(1704)

The phenol 15-1 (1.0 g, 4.90 mmol) was dissolved in concentratedsulfuric acid (4.8 mL) and cooled to 0° C. A 70% solution of nitric acid(0.38 mL, 5.90 mmol) was added dropwise to this solution causing ayellow colour change. The reaction was stirred at 0° C. for 1 h, then atRT for 1.5 h. Ice was added and the mixture was stirred for 1 h, thenfiltered to afford a yellow solid was washed with water (×2) and airdried to givehydroxy-3-isopropyl-8-nitro-4H-pyrido[1,2-a]pyrimidin-4-one 15-2 (0.78g, 60%). ¹H NMR (400 MHz, d₆-DMSO) δ1.21 (s, 3H), 1.22 (s, 3H), 3.05 (m,J=6.8 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.88 (s,1H). HPLC (254 nm): t_(R)=8.81 (96%).

8-Amino-9-hydroxy-3-isopropyl-4H-pyrido[1,2-a]pyrimidin-4-one (15-3)

To a stirred suspension of the nitro compound (15-2) (0.77 g, 3.50 mmol)in a 1:1 mixture of methanol and water (12 mL each) was added sodiumdithionite (3.24 g, 18.6 mmol) and the mixture was stirred under anitrogen atmosphere for 17 h. The majority of methanol was removed underreduced pressure before the precipitate was filtered and washed withwater (×3) and air dried. The desired product8-Amino-9-hydroxy-3-isopropyl-4H-pyrido[1,2-a]pyrimidin-4-one (15-3) wasisolated as a yellow solid (0.46 g, 60%). ¹H NMR (400 MHz, d₆-DMSO)δ1.25 (s, 3H), 1.27 (s, 3H), 3.13 (m, J=6.8 Hz, 1H), 5.82 (bs, 2H), 6.88(d, J=7.6 Hz, 1H), 7.98 (s, 1H), 8.45 (d, J=7.6 Hz, 1H).

4-Chloro-N-(9-hydroxy-3-isopropyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl)benzenesulfonamide15-4 (1717)

The reaction was conducted according to the general procedure aboveusing the amine (50 mg, 0.23 mmol) and 4-chlorobenzene sulfonyl chloride(60 mg, 0.30 mmol). Concentration gave a brown gum that was sonicated inwater, filtered, washed with water and air dried.4-Chloro-N-(9-hydroxy-3-isopropyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl)benzenesulfonamidewas obtained as a tan solid (38.4 mg, 51%). ¹H NMR (500 MHz, d₆-DMSO)δ1.13 (s, 3H), 1.15 (s, 3H), 2.98 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.97(bs, 1H), 7.62 (s, 1H), 7.67 (d, J=9.0 Hz, 2H), 7.99 (d, J=9.0 Hz, 2H),8.58 (d, J=8.0 Hz, 1H). MS (ESI) m/z: 394.0621 [M+H]. HPLC (254 nm):t_(R)=10.86 (82%).

TABLE 14 Compounds prepared according to Example 15 (Scheme15) MassCompound Structure MW Proton NMR Spec 1722

311.4 ¹H NMR (400 MHz, d6- DMSO) δ1.18 (s, 3H), 1.19 (s, 3H), 1.45 (t, J= 7.6 Hz, 3H), 3.88 (q, J = 7.6 Hz, 3H), 6.81 (bs, 1H), 6.88 (d, J = 8.0Hz, 1H), 8.00 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H). m/z 312.1 [M + H]⁺

Example 16

Fused Oxazole (16-1) (1708)

Carbonyldiimadazole (50 mg, 0.34 mmol) was added to a solution of theaniline 15-3 (50 mg, 0.23 mmol) in THE (1 mL) and heated to reflux for 2h. The reaction was cooled to room temperature over 1 h and concentratedunder reduced pressure to give a yellow solid. The solid was dissolvedin dichloromethane and extracted with a 2M aqueous solution of sodiumhydroxide (7 mL×3). The combined aqueous layers were taken to pH 5carefully using concentrated HCl solution, resulting in a whiteprecipitate forming in solution. The precipitate was filtered off andwashed with water and air dried to afford the fused oxazole (16-1)PB1708 (28 mg, 50%). ¹H NMR (400 MHz, d₆-DMSO) δ1.22 (s, 3H), 1.23 (s,3H), 3.09 (m, 1H), 7.31 (d, J=7.6 Hz, 1H), 8.15 (s, 1H), 8.85 (d, J=7.6Hz, 1H). MS (ESI) m/z: 246.0875 [M+H]⁺. HPLC (254 nm): t_(R)=7.09 (93%).

Example 17

9-Hydroxy-3-isopropyl-8-(4-methoxybenzylamino)-4H-pyrido[1,2-a]pyrimidin-4-one(17-1) (1716)

Potassium carbonate (40 mg, 0.31 mmol) was added to a stirred solutionof 4-methoxybenzyl chloride (40 mg, 0.25 mmol) and the aniline 15-3 (50mg, 0.23 mmol) in DMF (1 mL) and heated at 90° C. for 17 h. The reactionwas concentrated to give a dark brown gum that was diluted with ethylacetate and washed with water (5 mL) and brine (5 mL) and then dried(Na₂SO₄). Concentration under reduced pressure gave a brown gum that waspurified by flash chromatography on silica (5 g) eluting with a 4%solution of methanol in dichloromethane (400 mL). A yellow gum wasisolated and identified as9-hydroxy-3-isopropyl-8-(4-methoxybenzylamino)-4H-pyrido[1,2-a]pyrimidin-4-one(17-1) 1716 (20 mg, 25%). ¹H NMR (400 MHz, d₆-DMSO) δ1.21 (s, 3H), 1.21(s, 3H), 2.99 (m, 1H), 3.71 (s, 3H), 5.07 (s, 2H), 6.47 (bs, 1H), 6.79(d, J=7.6 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 8.07(s, 1H), 8.54 (d, J=7.6 Hz, 1H). MS (ESI) m/z: 340.1572 [M+H]⁺. HPLC(300 nm): t_(R)=10.15 (99%).

Example 18—Metallocomplexes

Copper and zinc metal complexes of various 9-hydroxy pyridopyrimidinecompounds can be prepared by stirring a solution of the pyridopyrimidinein a solvent together with Cu (II) or Zn (II) chloride. The resultingprecipitated product is filtered and dried to afford the desiredcomplexes.

Zinc Complex of 9-hydroxy-3-propyl-4H-pyridin[1,2-a]pyrimidin-4-one(1678)

To a stirred solution of9-hydroxy-3-propyl-4H-pyridin[1,2-a]pyrimidin-4-one (150 mg, 0.75 mmol)in EtOH (75 mL) was added a solution of zinc (II) chloride (100 mg, 0.75mmol) in H₂O (36 mL). After 10 min, a precipitate formed which wasremoved by filtration. The mother liquors were left to stand overnightin which time fine white crystals precipitated out of solution. Afterleaving for a further 7 days, the crystals were filtered off (91 mg) andwashed with cold ethanol to provide the desired zinc complex (1678). AnX-ray crystal structure was obtained.

TABLE 15 Compounds prepared according to Example 18 Compound StructureMW Analysis 1678

473.83 ¹H NMR (600 MHz, d6-DMSO) δ0.91 (t, J = 7.8 Hz, 3H), 1.59 (m,2h), 2.52 m, 2H), 6.84 (d, J = 7.2 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H),8.05 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H). 1692

472.00 IR(KBr, cm⁻¹): 3447 (coordinated water), 2922 (C − H), 1709 (C =O), 1683, 1618 (C = N), 1538, 1505, 1338, 1289, 1242, 1162, 1141, 1070,952, 750. 1700

558.0 ¹H NMR (600 MHz, d6-DMSO) δ0.96 (t, J = 7.2 Hz, 3H), 1.19 (s, 3H),1.20 (s, 3H), 1.71 (m, 2H), 2.74 (t, J = 7.2 Hz, 2H), 3.08 (m, 1H), 7.20(d, J = 6.6 Hz, 1H), 8.04 (d, J = 6.6 Hz, 1H), 8.08 (s, 1H) 1715

636.2 IR(KBr, cm⁻¹): 3441 (coordinated water), 3326 (NH), 2927 (C − H),2851, 1695 (C = O), 1644. 1613, 1528 (C = N), 1494, 1373, 1320, 1283,1134, 779, 673. 1718

554.1 IR(KBr, cm⁻¹): 3441 (coordinated water), 2954 (C − H), 1673 (C =O), 1600 (C = N), 1527. 1515, 1346, 1300, 1246, 1149, 832. 1719

470.0 IR(KBr, cm⁻¹): 3441 (coordinated water), 2954 (C − H), 1673 (C =O), 1600 (C = N), 1527. 1515, 1346, 1300, 1246, 1149, 832. 1744

638.0 ¹H NMR (400 MHz, d6-DMSO) δ1.31 (m, 6H), 1.65 (m, 1H), 1.60 (m,2H), 1.84 (m, 2H), 3.80 (m, 1H), 7.15 (d, J = 5.2 Hz, 1H), 7.43 (t, J =7.2 Hz, 1H), 8.24 (d, J = 7.2 Hz), 8.82 (s, 1H), 8.99 (d, J = 7.2 Hz,1H). 1745

610.0 ¹H NMR (500 MHz, d6-DMSO) δ1.47 (m, 2H), 1.59 (m, 2H), 1.91 (m,2H), 4.24 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 6.0 Hz, 1H),8.23 (m, 1H), 8.85 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H). m/z 609.1[M + H]⁺1748

586.0 ¹H NMR (500 MHz, d6-DMSO) δ0.90 (t, J = 6.0 Hz, 3H), 1.33 (m, 2H),1.49 (m, 2H), 1.51 (m, 2H), 3.36 (m, 2H, obscured), 7.15 (d, J = 5.6 Hz,1H), 7.44 (t, J = 5.6 Hz, 1H), 8.24 (d, J = 5.6 Hz, 1H), 8.87 (s, 1H),8.93 (m, 1H)

Example 19

Compound 1761(2S,3S,4S,5R,6S)-2-(Methoxycarbonyl)-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-3,4,5-trylTriacetate (19-2)

Caesium carbonate (0.65 g, 2.0 mmol) was added to a stirred solution of9-hydroxy-3-propyl-4H-pyridin[1,2-a]pyrimidin-4-one (19-1) (0.13 g, 0.67mmol) and(3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (0.80 g, 2.0 mmol) in acetonitrile (7.0 mL). The mixture wasstirred at room temperature under an argon atmosphere for 6 days. Water(5.0 mL) was added to the reaction which was then extracted withdichloromethane (10 mL×3). The organic layers were dried (sodiumsulphate) and concentrated under reduced pressure to give a brown gum.Purification by chromatography on silica (10 g), eluting with a 20:1solution of dichloromethane/methanol afforded(2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-3,4,5-tryltriacetate (19-2) as a cream solid (0.30 g, 86%). ¹H NMR (600 MHz,CDCl₃) δ 0.92 (t, J=7.2 Hz, 3H), 0.62 (m, 2H), 1.98 (s, 3H), 2.00 (s,3H), 2.05 (s, 3H), 2.56 (m, 2H), 3.66 (s, 3H), 4.07 (d, J=9.0 Hz, 1H),5.30-5.33 (m, 3H), 5.43 (d, J=6.6 Hz, 1H), 6.94 (t, J=7.2 Hz, 1H), 7.36(d, J=1.2 Hz, 1H), 8.09 (s, 1H), 8.76 (dd, J=1.2, 7.2 Hz, 1H).

(2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-2-carboxylicAcid (19-3)

A 2M aqueous solution of potassium carbonate (0.29 mL, 0.58 mmol) wasadded to a solution of A (0.05 g, 0.10 mmol) dissolved in THE/water(4:1, 8 mL) at 0° C. The reaction was stirred at this temperature for 5min then warmed to room temperature and stirred for 2 h. The reactionwas then neutralised with Amberlite IRA (H*) resin and filtered. Theresin was washed with methanol (5 mL×2) and the filtrates wereconcentrated. Chromatography (silica, 20 g), eluting with a mixture ofethyl acetate, methanol and water (7:2:1, 300 mL) afforded(2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-2-carboxylicacid (19-3) as cream, gummy solid (78 mg, 74%). ¹H NMR (600 MHz,d₆-DMSO) δ 0.89 (t, J=7.8 Hz, 3H), 1.59 (m, 2H), 1.90 (s, 3H), 1.98 (s,3H), 1.99 (s, 3H), 2.50 (m, 2H), 3.98 (d, J=10.2 Hz, 1H), 5.09 (t, J=9.6Hz, 1H), 5.13 (t, J=7.8 Hz, 1H), 5.26 (t, J=9.6 Hz, 1H), 5.58 (d, J=8.4Hz, 1H), 7.25 (t, J=7.2 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 8.23 (s, 1H),8.66 (d, J=7.2 Hz, 1H).

(2S,3S,4S,5R,6S)-3,4,5-Trihydroxy-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-2-carboxylicAcid (1761)

Triethylamine (0.21 mL, 1.50 mmol) was added to a stirred solution ofthe acid 19-3 (0.15 g, 0.30 mmol) in methanol (1.5 mL) and headed underargon for 17 h. The reaction was cooled in an ice bath and thesubsequent white precipitate was filtered off and washed with minimalcold methanol.(2S,3S,4S,5R,6S)-3,4,5-Trihydroxy-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-2-carboxylicacid (1761) was isolated as a white solid (54 mg, 47%). ¹H NMR (600 MHz,d₆-DMSO) δ 0.90 (t, J=7.2 Hz, 3H), 1.59 (m, 2H), 2.50 (m, 2H), 3.12 (t,J=9.0 Hz, 1H), 3.26-3.31 (m, 2H), 3.44 (d, J=9.6 Hz, 1H), 5.02 (bs, 1H),5.06 (d, J=7.8 Hz, 1H), 5.41 (d, J=5.4 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H),7.42 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 8.61 (d, J=6.6 Hz, 1H). 13C NMR(150 MHz, d₆-DMSO) δ 14.11, 21.75, 30.20, 72.41, 73.38, 74.01, 77.34,101.05, 115.59, 116.61, 117.81, 119.92, 144.80, 150.10, 151.48, 157.85,171.22. MS (ESI) m/z: 381.1302 [M+H]⁺. HPLC (300 nm): t_(R)=4.99 (97%).

Example 20

Compound 1756 (Glycoside of9-hydroxy-3-propyl-4H-pyridin[1,2-a]pyrimidin-4-one 19-1)(2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-3,4,5-triylTriacetate (20-1)

Caesium carbonate (2.4 g, 7.3 mmol) was added to a stirred solution of9-hydroxy-3-propyl-4H-pyridin[1,2-a]pyrimidin-4-one (19-1) (0.50 g, 2.5mmol) and(2R,3S,4S,5R)-2-(acetoxymethyl)-4,6-dihydroxytetrahydro-2H-pyran-3,5-diyldiacetate (3.0 g, 7.3 mmol) in acetonitrile (24.0 mL). The mixture wasstirred at room temperature under an argon atmosphere for 6 days. Water(30.0 mL) was added to the reaction which was then extracted withdichloromethane (10 mL×3). The organic layers were dried (sodiumsulphate) and concentrated under reduced pressure to give a brown oil.Purification by chromatography on silica (40 g), eluting with a 20:1solution of dichloromethane/methanol (500 mL) afforded2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-oxo-3-propyl-4H-pyrido[1,2-a]pyrimidin-9-yloxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (20-1) as a cream solid (0.98 g, 75%). ¹H NMR (600 MHz,CDCl₃) δ 0.91 (t, J=7.2 Hz, 3H), 0.62 (m, 2H), 1.97 (s, 6H), 2.00 (s,3H), 2.05 (s, 3H), 2.56 (m, 2H), 3.75 (m, 1H), 4.11 (dd, J=2.4, 12.0 Hz,1H), 4.20 (dd, J=4.8, 12.6 Hz, 1H), 5.13 (m, 1H), 5.31 (m, 3H), 6.93 (t,J=7.8 Hz, 1H), 7.29 (dd, J=1.2, 7.2 Hz, 1H), 8.11 (s, 1H), 8.76 (dd,J=1.2, 7.2 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 14.52, 21.23, 21.28,21.34, 21.47, 22.41, 31.05, 62.38, 68.85, 71.64, 72.95, 72.97, 100.66,114.28, 120.10, 121.31, 123.34, 149.42, 152.08, 158.72, 170.02, 170.21,170.87, 171.82.

3-Propyl-9-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one(1756)

Triethylamine (0.48 mL, 3.50 mmol) was added to a stirred solution ofthe acetate 20-1 (0.37 g, 0.69 mmol) in methanol (7.0 mL) and headedunder argon for 17 h. In this time a precipitate was evident in thereaction mixture. The reaction was cooled in an ice bath and the whiteprecipitate was filtered off and washed with minimal cold methanol. Thesolid was recrystallised from methanol to yield3-propyl-9-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one(1756) as a white solid (151 mg, 60%). ¹H NMR (600 MHz, d₆-DMSO) δ 0.89(t, J=7.2 Hz, 3H), 1.58 (m, 2H), 2.53 (m, 2H), 3.16 (m, 1H), 3.32 (m,2H), 3.46 (m, 1H), 3.68 (m, 1H), 4.56 (m, 1H), 5.06 (d, J=4.8 Hz, 1H),5.11-5.12 (m, 2H), 5.51 (d, J=4.8 Hz, 1H), 7.22 (d, J=6.6 Hz, 1H), 7.43(d, J=7.2 Hz, 1H), 8.22 (s, 1H), 8.61 (d, J=6.6 Hz, 1H). ¹³C NMR (150MHz, d₆-DMSO) 14.11, 21.76, 30.18, 61.05, 69.06, 73.46, 77.16, 77.73,100.78, 115.52, 116.19, 117.94, 119.96, 142.75, 144.80, 149.84, 151.39,157.63. MS (ESI) m/z: 367.1509 [M+H]⁺. HPLC (300 nm): t_(R)=4.

TABLE 16 Compound prepared according to Example 20 Compound Structure MWAnalysis 1862

458.42

Example 21—Assessment of Properties Compounds

The following Assays were used to assess the properties of the compoundsto determine their suitability for use in the methods of the presentinvention.

Assay 1. Hydrogen Peroxide Assay

H₂O₂ is a strong oxidizer and a highly reactive oxygen species that isknown to be toxic to surrounding proteins and organelles, inhibitingtheir function. The hydrogen peroxide (H₂O₂) inhibition assay is afluorescence assay which evaluates the ability of a test compound toinhibit the generation of H₂O₂ by the presence of copper and a reducingsubstrate, being either dopamine or ascorbic acid. In the assay, copperin the form of CuCl₃ is allowed to react with ascorbic acid or dopamineby incubating for 1 hr at 37° C. in the presence of the fluorescingcompound DCF and horseradish peroxidase. H₂O₂ generated by the system isassessed by measuring the specific fluorescence profile at theexcitation and emission wavelengths of 485 and 530 nm respectively, inthe presence of test compound. Test compounds were dissolved in DMSO andtested at concentrations of 0.4 μM. Test compounds are ranked accordingto their capacity to inhibit H₂O₂ generated by the system where lowervalues reflect greater ability to inhibit H₂O₂ production.

Assay 2. Physiochemical Properties

c Log P Values

Theoretical Log P values were determined using the ACD Log P software.The values quoted have been calculated from an untrained database andrefer to the unionised species.

E Log D

Effective Log D values were measured using a chromatographic methodemploying a SUPELCOSIL LC-ABZ column using an octanol saturated mobilephase at pH 7.4. See F. Lombardo et al, J. Med. Chem. 2000, 43,2922-2928.

The following table provides the properties and structures of compoundsof the present invention. The properties of the HCl salt were tested forthose compounds in the table where the MW of the HCl salt is provided.

TABLE 17 Properties H₂0₂ IC₅₀ (μM)^(a) Fe-ASC % Fe-DA % (cf. 0.4 uMFe/Asc or Fe/DA) Compound cf. CQ (CQ = 100%) Parent MW/PSA ClogP 12350.29 238.68 2.43 86% ASC 1394 0.72 317.38 3.56 96% ASC 1398 1.29 206.2039% ASC 1399 0.23 205.21 −0.16 30% ASC 1400 0.33 Parent: 219.24 0.37 32%ASC HCl Salt: 255.69 1401 0.42 Parent: 219.24 0.31 55% ASC HCl Salt:255.69 1402 1.68 288.35 1.31 36% ASC HCl salt 324.81 1403 1.7 259.311.50 49% ASC HCl salt 295.76 1404 0.28 243.267 0.91 37% ASC HCl salt279.72 1405 0.29 247.3 1.43 35% ASC HCl salt 283.75 1406 1.14 315.751.71 HCl salt 352.21 1407 0.15 Parent: 233.27 0.90 31% ASC HCl Salt:269.72 1408 0.43 Parent: 247.29 1.30 HCl Salt: 283.74 1409 0.14 Parent:299.30 1.14 HCl Salt: 335.75 1410 0.43 Parent: 303.40 3.55 62% ASC HClSalt: 339.85 1411 0.33 Parent: 245.28 0.82 36% ASC HCl Salt: 281.73 14120.13 Parent: 318.37 0.43 29% ASC HCl salt: 391.29 1413 0.19 Parent:261.32 1.96 42% ASC HCl Salt: 297.77 1414 <0.1 Parent: 282.3 −0.50 29%ASC HCl Salt: 318.74 1415 <0.1 Parent: 296.33 0.44 34% ASC HCl Salt:332.77 1416 0.1 Parent: 282.2 −0.50 52% ASC HCl salt: 318.76 1417 0.13Parent: 288.35 0.86 29% ASC HCl salt: 361.27 1418 0.24 Parent: 304.350.21 30% ASC HCl Salt: 377.27 1422 0.68 275.31 1.97 63% ASC 1423 0.38247.26 0.91 45% ASC 1424 0.8 219.2452 0.31 48% ASC HCl salt: 243.69 14250.34 261.28 1.31 Cu 212% ASC Zn 69% ASC 76% 1426 0.32 302.33 0.90 Cu212% ASC Zn 121% ASC 62% 1427 0.18 310.31 0.45 Cu 212% ASC Zn 61% ASC74% 1428 0.43 259.27 0.83 Cu 212% ASC Zn 74% ASC 75% 1429 0.39 329.742.53 Cu 54% ASC Zn 57% ASC 148% 1430 2.28 204.23 1.95 Cu 184% ASC Zn 98%ASC 44% 1431 0.44 325.33 1.74 71% ASC 70% 1432 0.41 339.31 1.79 65% ASC66% 1433 0.39 223.23 0.38 152% ASC 73% 1434 3.16 190.2 1.42 135% ASC 95%1435 0.23 259.31 1.314 133% ASC HCl salt: 295.75 90% 1436 0.21 273.291.32 190% ASC 101% 1437 0.47 331.28 2.11 71% ASC 71% 1438 0.24 275.352.487 143% ASC HCl salt: 311.8 47% 1439 >10 247.3 1.366 156% ASC HClsalt: 283.75 68% 1440 0.69 289.34 2.50 66% ASC 48% 1441 0.47 263.260.05 >224% ASC 55% 1442 0.24 281.32 1.0 128% ASC 58% 1443 0.25 347.80.92 116% ASC 52% 1444 0.35 303.27 2.05 105% ASC 53% 1445 <0.1 219.2−0.147 176% ASC 45% 1446 0.34 296.29 0.32 218% ASC 56% 1447 0.24 296.290.35 112% ASC 52% 1448 0.46 268.28 137% ASC 66% 1449 0.47 267.29 144%ASC 71% 1450 0.38 296.29 0.35 126% ASC 55% 1451 0.58 285.27 1.87 136%ASC 67% 1452 0.54 364.19 3.25 60% ASC 49% 1453 0.34 363.30 2.70 79% ASC59% 1454 1 331.28 2.04 65% ASC 46% 1455 0.35 295.34 1.88 82% ASC 47%1456 0.39 273.34 1.88 122% ASC 58% 1457 0.39 350.21 2.43 127% 61% 14580.58 287.35 2.49 137% ASC 43% 1459 0.33 317.30 1.29 110% ASC HCl salt:353.75 48% 1460 0.44 287.32 1.88 92% ASC 29% 1461 0.49 301.35 2.50 59%ASC 57% 1462 0.46 305.38 3.03 72% ASC 54% 1463 0.59 341.37 0.658 158%ASC 73% 1464 0.47 365.31 2.03 135% ASC HCl salt: 401.76 47% 1466 0.34233.27 0.807 >234% ASC HCl salt: 269.72 47% 1467 0.44 313.33 1.642 74%ASC 42% 1468 0.21 287.36 2.372 169% ASC HCl salt: 323.81 39% 1469 0.5329.789 2.212 63% ASC 43% 1470 0.35 247.299 1.399 >234% ASC 38% 1471 0.3273.34 2.000 125% ASC HCl salt: 309.79 62% 1476 0.23 310.36 0.908 122%ASC 46% 1478 3.12 295.34 1.49 198% ASC 75% 1479 0.46 313.33 2.21 147%ASC HCl salt 349.78 42% 1485 0.53 261.33 1.895 159% ASC HCl salt: 297.7857% 1488 1.95 283.12 2.55 114% ASC 69% 1490 0.4 261.326 1.865 178% ASCHCl salt: 297.776 55% 1491 0.3 257.294 1.4072 >222% ASC HCl salt: 293.7448% 1500 0.36 327.36 2.718 171% ASC HCl salt: 363.81 42% 1503 0.23301.38 2.991 204% ASC HCl salt: 337.84 42% 1504 0.31 310.35 0.9412 160%ASC 2HCl salt: 383.26 33% 1506 >10 273.34 2.02025 161% ASC HCl salt:309.79 48% 1508 0.17 287.357 2.519 148% ASC HCl salt: 323.807 32% 1515 1368.404 2.647 103% ASC HCl salt: 441.305 54% 1516 0.3 313.326 2.219 102%ASC HCl salt: 349.776 52% 1517 0.35 313.326 2.219 105% ASC HCl salt:349.776 55% 1518 0.58 329.781 2.789 84% ASC HCl salt: 366.23 49% 15190.35 343.807 3.288 100% ASC HCl salt: 380.26 47% 1521 >10 287.357 2.339123% ASC HCl salt: 323.807 50% 1522- 0.44 382.431 3.146 156% ASC HClsalt: 455.341 47% 1523 0.7 301.383 2.838 135% ASC HCl salt: 337.833 49%1525 0.32 327.36 2.718 105% ASC HCl salt: 363.81 46% 1527 0.33 327.362.718 133% ASC HCl salt: 363.81 64% 1531 1.48 296.13 1.894 HCl salt:332.77 1532 0.9 259.26 −0.145 1533 1.19 273.29 0.414 1591 220.22 0.661595 421.9 3.71 1596 281.31 2.00 1597 326.39 3.07 1598 312.37 1599283.12 2.91 1600 299.32 1.42 1601 312.37 2.67 1602 284.31 1.81 1603299.32 1.55 1604 253.68 1.03 1605 290.31 1.99 1606 361.4 2.80 1607238.67 2.76 1608 281.74 2.09 1609 347.7 2.95 1610 333.74 1.83 1611364.57 3.54 1612 384.64 3.15 1613 232.29 3.00 1614 267.71 1.63 1615361.4 2.93 1616 361.4 3.23 1617 339.4 2.93 1618 402.85 3.37 2HCl 475.771619 228.25 1.39 1620 232.28 3.06 1621 244.30 3.09 1622 278.73 3.82 1623230.26 2.54 1624 264.71 3.26 1625 228.25 1.39 1626 339.39 2.64 1627287.36 2.32 1628 344.41 1.67 1629 Cu 204% ASC 315.75 2.60 Zn 130% ASC1630 Cu 213% ASC 333.77 2.02 Zn 129% ASC 1631 Cu 248% ASC 261.33 1.82 Zn101% ASC 1632 Cu 228% ASC 261.33 1.69 Zn 106% ASC 1633 Cu 17% ASC 284.321.61 Zn 140% ASC 1634 295.72 0.95 1635 279.72 1.67 HCl MW: 316.18 1636420.84 3.52 1637 453.75 4.66 1638 414.89 3.15 1639 298.31 3.77 1640329.29 2.23 1641 281.31 2.13 1642 301.38 2.89 1643 238.67 2.63 1644421.28 3.03 1645 303.36 1.73 1646 234.1 0.97 1647 289.37 2.87 1648298.34 1.67 1649 248.23 1.46 1650 282.25 2.61 1651 298.34 1.54 1652286.35 3.14 1653 270.28 2.67 1654 284.31 3.37 1655 281.31 2.00 1656303.36 1.60 1657 356.38 0.94 1658 318.37 1.22 1659 298.31 3.64 1660355.36 3.17 1661 327.33 2.2 1662 238.65 2.68 1663 224.64 2.15 1664339.35 2.39 1665 350.54 2.92 1666 330.11 2.74 1667 266.72 3.73 1668348.32 4.38 1669 330.38 1.10 1670 307.78 HCl salt MW: 344.24 1671 296.363.72 1672 300.74 3.71 1673 319.74 1.407 1674 252.27 2.54 1678 473.833.57 1679 275.35 2.56 1680 281.31 2.13 1681 316.30 3.91 1682 332.40 1.751683 323.39 1684 372.2 1685 220.2 0.38 1686 254.67 1.11 1687 280.75 3.611688 392.62 4.51 1689 434.70 5.51 1690 343.81 3.58 1691 277.32 0.16 1692472.00 1698 212.63 0.969 1699 398.89 2.42 1700 557.99 6.43 1701 254.671.39 1703 283.67 2.35 1704 219.24 1.74 1708 245.23 0.81 1710 291.3 0.791711 310.31 0.95 1712 370.38 1.75 1713 373.88 0.98 1714 357.88 2.87 1715636.16 2.81 1716 339.39 3.53 1717 393.84 3.56 1718 554.14 6.22 1719469.98 3.11 1720 HCl salt MW: 420.38 3.52 383.92 1721 HCl salt MW:429.34 1.97 392.88 1722 311.36 1.71 1723 414.41 3.62 1724 402.41 1.111744 644.0 1745 612.0 1748 585.95 1756 366.37 0.054 1761 380.35 −0.421862 458.42 −1.61

REFERENCES

-   Bush A I, Goldstein L E. Specific metal-catalysed protein oxidation    reactions in chronic degenerative disorders of ageing: focus on    Alzheimer's disease and age-related cataracts. Novartis Found Symp.    2001; 235:26-38; discussion 38-43.

It is to be understood that, if any prior art publication is referred toherein, such reference does not constitute an admission that thepublication forms a part of the common general knowledge in the art, inAustralia or any other country.

In the claims which follow and in the preceding description of theinvention, except where the context requires otherwise due to expresslanguage or necessary implication, the word “comprise” or variationssuch as “comprises” or “comprising” is used in an inclusive sense, i.e.to specify the presence of the stated features but not to preclude thepresence or addition of further features in various embodiments of theinvention.

What is claimed is:
 1. A compound of formula Ic:

in which R² is (CH₂)_(n)SC═SNR⁹R¹⁰; R⁵ is H or C₁₋₄ alkyl; R⁶ is H,halo, (CH₂)_(n) 5 or 6 membered heterocyclyl in which the heterocyclylgroup is optionally substituted or C₂₋₄ alkynyl; provided that one of R⁵and R⁶ is not hydrogen; R⁸ is H, SO₂ aryl in which the aryl group isoptionally substituted, C₁₋₄ alkyl or (CH₂)_(n) aryl; R⁹ and R¹⁰ areindependently selected from H, C₁₋₈ alkyl optionally interrupted with O,CN, (CH₂)_(n) aryl in which the aryl group is optionally substituted andin which the aryl group is optionally fused with a 5 or 6 memberedheterocyclyl, (CH₂)_(n) C₃₋₈ cycloalkyl in which the cycloalkyl group isoptionally substituted, (CH₂)_(n) 5 or 6 membered heterocyclyl in whichthe heterocyclyl group is optionally substituted, SO₂ aryl in which thearyl group is optionally substituted and C₁₋₄ alkoxy; n is 0, 1, 2 or 3;wherein optional substituents are selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heterocyclyl, halo,haloC₁₋₆alkyl, CF₃, haloC₃₋₆cycloalkyl, haloC₂₋₆alkenyl,haloC₂₋₆alkynyl, haloaryl, haloheterocycylyl, hydroxy, C₁₋₆ alkoxy,OCF₃, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, aryloxy, heterocyclyloxy, carboxy,haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy, haloC₂₋₆alkynyloxy, haloaryloxy,nitro, nitroC₁₋₆alkyl, nitroC₂₋₆alkenyl, nitroaryl, nitroheterocyclyl,azido, amino, C₁₋₆alkylamino, C₂₋₆alkenylamino, C₂₋₆alkynylamino,arylamino, heterocyclylamino acyl, C₁₋₆alkylacyl, C₂₋₆alkenylacyl,C₂₋₆alkynylacyl, arylacyl, heterocyclylacyl, acylamino, acyloxy,aldehydo, C₁₋₆alkylsulphonyl, arylsulphonyl, C₁₋₆alkylsulphonylamino,arylsulphonylamino, C₁₋₆alkylsulphonyloxy, arylsulphonyloxy,C₁₋₆alkylsulphenyl, C₂₋₆alklysulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, C₁₋₆alkylthio, arylthio, acylthio and cyano;each 5 or 6 membered heterocyclyl group may have 1, 2, 3 or 4heteroatoms selected from 0, S and N and may be saturated, unsaturatedor aromatic; or a pharmaceutically acceptable salts, stereoisomer orgeometric isomer thereof.
 2. A compound according to claim 1 which is acompound of formula Ic wherein R² is (CH₂)_(n)SC═SNR⁹R¹⁰; R⁵ is H orC₁₋₄alkyl; and R⁶ is halo.
 3. A compound according to claim 2 wherein R⁶is chloro.
 4. A compound of according to claim 1 which is selected from:


5. A compound of formula IIc

in which R² is (CH₂)_(n)SC═SNR⁹R¹⁰; R⁵ is H or C₁₋₄ alkyl; R⁶ is H,halo, (CH₂)_(n) 5 or 6 membered heterocyclyl in which the heterocyclylgroup is optionally substituted or C₂₋₄ alkynyl; provided that one of R⁵and R⁶ is not hydrogen; R⁸ is H, SO₂ aryl in which the aryl group isoptionally substituted, C₁₋₄ alkyl or (CH₂)_(n) aryl; R⁹ and R¹⁰ areindependently selected from H, C₁₋₈ alkyl optionally interrupted with O,CN, (CH₂)_(n) aryl in which the aryl group is optionally substituted andin which the aryl group is optionally fused with a 5 or 6 memberedheterocyclyl, (CH₂)_(n) C₃₋₈ cycloalkyl in which the cycloalkyl group isoptionally substituted, (CH₂)_(n) 5 or 6 membered heterocyclyl in whichthe heterocyclyl group is optionally substituted, SO₂ aryl in which thearyl group is optionally substituted and C₁₋₄ alkoxy; n is 0, 1, 2 or 3;wherein optional substituents are selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heterocyclyl, halo,haloC₁₋₆alkyl, CF₃, haloC₃₋₆cycloalkyl, haloC₂₋₆alkenyl,haloC₂₋₆alkynyl, haloaryl, haloheterocycylyl, hydroxy, C₁₋₆ alkoxy,OCF₃, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, aryloxy, heterocyclyloxy, carboxy,haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy, haloC₂₋₆alkynyloxy, haloaryloxy,nitro, nitroC₁₋₆alkyl, nitroC₂₋₆alkenyl, nitroaryl, nitroheterocyclyl,azido, amino, C₁₋₆alkylamino, C₂₋₆alkenylamino, C₂₋₆alkynylamino,arylamino, heterocyclylamino acyl, C₁₋₆alkylacyl, C₂₋₆alkenylacyl,C₂₋₆alkynylacyl, arylacyl, heterocyclylacyl, acylamino, acyloxy,aldehydo, C₁₋₆alkylsulphonyl, arylsulphonyl, C₁₋₆alkylsulphonylamino,arylsulphonylamino, C₁₋₆alkylsulphonyloxy, arylsulphonyloxy,C₁₋₆alkylsulphenyl, C₂₋₆alklysulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, C₁₋₆alkylthio, arylthio, acylthio and cyano;each 5 or 6 membered heterocyclyl group may have 1, 2, 3 or 4heteroatoms selected from O, S and N and may be saturated, unsaturatedor aromatic; and M is transition metal; or a pharmaceutically acceptablesalts, stereoisomers or geometric isomer thereof.
 6. A compound offormula Id:

Id R² is H, (CH₂)_(n)NR⁹R¹⁰, C₁₋₄ alkyl optionally interrupted withoxygen or (CH₂)_(n)SC═SNR⁹R¹⁰; R³ is C₁₋₄ alkyl optionally interruptedwith oxygen, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, (CH₂)_(n)aryl in which thearyl group is optionally substituted, (CH₂)_(n) aryl in which the arylgroup is optionally substituted and in which the aryl group isoptionally fused with a 5 or 6 membered heterocyclyl, C(O)NR⁹R¹⁰,(CH₂)_(n) NR⁹R¹⁰ or C(O)NH—N═CR⁹R¹⁰; R⁶ is H, halo, (CH₂)_(n) 5 or 6membered heterocyclyl in which the heterocyclyl group is optionallysubstituted or C₂₋₄ alkynyl; R⁷ is (CH₂)_(n) 5 membered heterocyclyl inwhich the heterocyclyl group is optionally substituted, C₁₋₄ alkyl inwhich the alkyl group is optionally substituted, C₂₋₄ alkynyl, NO₂,NR⁵SO₂ aryl in which the aryl group is optionally substituted or NR⁵SO₂C₁₋₄alkyl in which the alkyl group is optionally substituted; R⁸ is H,SO₂ aryl in which the aryl group is optionally substituted, C₁₋₄ alkylor (CH₂)_(n) aryl; or R⁷ together with the carbon atom to which it isattached and R⁸ together with the oxygen atom to which it is attachedfrom a 5 membered ring; R⁹ and R¹⁰ are independently selected from H,C₁₋₈ alkyl optionally interrupted with O, CN, (CH₂)_(n) aryl in whichthe aryl group is optionally substituted and in which the aryl group isoptionally fused with a 5 or 6 membered heterocyclyl, (CH₂)_(n) C₃₋₈cycloalkyl in which the cycloalkyl group is optionally substituted,(CH₂)_(n) 5 or 6 membered heterocyclyl in which the heterocyclyl groupis optionally substituted, SO₂ aryl in which the aryl group isoptionally substituted and C₁₋₄ alkoxy; or R⁹ and R¹⁰ together with thenitrogen atom to which they are attached form a 5 or 6 memberedheterocyclyl in which the heterocyclyl group is optionally substituted;m is 1, 2 or 3; and n is 0, 1, 2 or 3; wherein optional substituents areselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, heterocyclyl, halo, haloC₁₋₆alkyl, CF₃, haloC₃₋₆cycloalkyl,haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, haloaryl, haloheterocycylyl, hydroxy,C₁₋₆ alkoxy, OCF₃, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, aryloxy,heterocyclyloxy, carboxy, haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy,haloC₂₋₆alkynyloxy, haloaryloxy, nitro, nitroC₁₋₆alkyl,nitroC₂₋₆alkenyl, nitroaryl, nitroheterocyclyl, azido, amino,C₁₋₆alkylamino, C₂₋₆alkenylamino, C₂₋₆alkynylamino, arylamino,heterocyclylamino acyl, C₁₋₆alkylacyl, C₂₋₆alkenylacyl, C₂₋₆alkynylacyl,arylacyl, heterocyclylacyl, acylamino, acyloxy, aldehydo,C₁₋₆alkylsulphonyl, arylsulphonyl, C₁₋₆alkylsulphonylamino,arylsulphonylamino, C₁₋₆alkylsulphonyloxy, arylsulphonyloxy,C₁₋₆alkylsulphenyl, C₂₋₆alklysulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, C₁₋₆alkylthio, arylthio, acylthio and cyano;each 5 or 6 membered heterocyclyl group may have 1, 2, 3 or 4heteroatoms selected from O, S and N and may be saturated, unsaturatedor aromatic; or a pharmaceutically acceptable salts, stereoisomers orprodrugs geometric isomer thereof.
 7. A compound according to claim 6wherein R² is C₁₋₄alkyl; R³ is C₁₋₄alkyl or benzyl; R⁶ is halo; R⁷ is 5or 6 membered optionally substituted heterocyclyl in which theheterocyclyl group is optionally substituted; and R⁸ is H or C₁₋₄alkyl.8. A compound according to claim 7 wherein R² is methyl.
 9. A compoundaccording to claim 7 wherein R⁶ is chloro.
 10. A compound according toclaim 7 wherein R⁸ is propyl.
 11. A compound according to claim 6 whichis selected from:


12. A compound of formula IId:

in which R² is H, (CH₂)_(n)NR⁹R¹⁰, C₁₋₄ alkyl optionally interruptedwith oxygen or (CH₂)_(n)SC═SNR⁹R¹⁰; R³ is C₁₋₄ alkyl optionallyinterrupted with oxygen, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, (CH₂)_(n)aryl inwhich the aryl group is optionally substituted, (CH₂)_(n)aryl in whichthe aryl group is optionally substituted and in which the aryl group isoptionally fused with a 5 or 6 membered heterocyclyl, C(O)NR⁹R¹⁰,(CH₂)_(n) NR⁹R¹⁰ or C(O)NH—N═CR⁹R¹⁰; R⁶ is H, halo, (CH₂)_(n) 5 or 6membered heterocyclyl in which the heterocyclyl group is optionallysubstituted or C₂₋₄ alkynyl; R⁷ is (CH₂)_(n) 5 membered heterocyclyl inwhich the heterocyclyl group is optionally substituted, C₁₋₄ alkyl inwhich the alkyl group is optionally substituted, C₂₋₄ alkynyl, NO₂NR⁵SO₂ aryl in which the aryl group is optionally substituted or NR⁵SO₂C₁₋₄alkyl in which the alkyl group is optionally substituted; R⁸ is H,SO₂ aryl in which the aryl group is optionally substituted, C₁₋₄ alkylor (CH₂)_(n) aryl; or R⁷ together with the carbon atom to which it isattached and R⁸ together with the oxygen atom to which it is attachedfrom a 5 membered ring; R⁹ and R¹⁰ are independently selected from H,C₁₋₈ alkyl optionally interrupted with O, CN, (CH₂O)_(n) aryl in whichthe aryl group is optionally substituted and in which the aryl group isoptionally fused with a 5 or 6 membered heterocyclyl, (CH₂)_(n) C₃₋₈cycloalkyl in which the cycloalkyl group is optionally substituted,(CH₂)_(n) 5 or 6 membered heterocyclyl in which the heterocyclyl groupis optionally substituted, SO₂ aryl in which the aryl group isoptionally substituted and C₁₋₄ alkoxy; or R⁹ and R¹⁰ together with thenitrogen atom to which they are attached form a 5 or 6 memberedheterocyclyl in which the heterocyclyl group is optionally substituted;m is 1, 2 or 3; and n is 0, 1, 2 or 3; wherein optional substituents areselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, heterocyclyl, halo, haloC₁₋₆alkyl, CF₃ haloC₃₋₆cycloalkyl,haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, haloaryl, haloheterocycylyl, hydroxy,C₁₋₆ alkoxy, OCF₃, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, aryloxy,heterocyclyloxy, carboxy, haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy,haloC₂₋₆alkynyloxy, haloaryloxy, nitro, nitroC₁₋₆alkyl,nitroC₂₋₆alkenyl, nitroaryl, nitroheterocyclyl, azido, amino,C₁₋₆alkylamino, C₂₋₆alkenylamino, C₂₋₆alkynylamino, arylamino,heterocyclylamino acyl, C₁₋₆alkylacyl, C₂₋₆alkenylacyl, C₂₋₆alkynylacyl,arylacyl, heterocyclylacyl, acylamino, acyloxy, aldehydo,C₁₋₆alkylsulphonyl, arylsulphonyl, C₁₋₆alkylsulphonylamino,arylsulphonylamino, C₁₋₆alkylsulphonyloxy, arylsulphonyloxy,C₁₋₆alkylsulphenyl, C₂₋₆alklysulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, C₁₋₆alkylthio, arylthio, acylthio and cyano;each 5 or 6 membered heterocyclyl group may have 1, 2, 3 or 4heteroatoms selected from O, S and N and may be saturated, unsaturatedor aromatic; and M is transition metal; or a pharmaceutically acceptablesalts, stereoisomer or geometric isomer thereof.
 13. A compound havingthe formula:

in which R² is (CH₂)_(n)NR⁹R¹⁰; R⁵ is H or C₁₋₄ alkyl; R⁶ is H, halo,(CH₂)_(n) 5 or 6 membered heterocyclyl in which the heterocyclyl groupis optionally substituted or C₂₋₄ alkynyl; provided that one of R⁵ andR⁶ is not hydrogen; R⁸ is H, SO₂ aryl in which the aryl group isoptionally substituted, C₁₋₄ alkyl or (CH₂)_(n) aryl; R⁹ and R¹⁰ areindependently selected from H, C₁₋₈ alkyl optionally interrupted with O,CN, (CH₂)_(n) aryl in which the aryl group is optionally substituted andin which the aryl group is optionally fused with a 5 or 6 memberedheterocyclyl, (CH₂)_(n) C₃₋₈ cycloalkyl in which the cycloalkyl group isoptionally substituted, (CH₂)_(n) 5 or 6 membered heterocyclyl in whichthe heterocyclyl group is optionally substituted, SO₂ aryl in which thearyl group is optionally substituted and C₁₋₄ alkoxy; n is 1,2 or 3;wherein optional substituents are selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heterocyclyl, halo,haloC₁₋₆alkyl, CF₃, haloC₃₋₆cycloalkyl, haloC₂₋₆alkenyl,haloC₂₋₆alkynyl, haloaryl, haloheterocycylyl, hydroxy, C₁₋₆ alkoxy,OCF₃, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, aryloxy, heterocyclyloxy, carboxy,haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy, haloC₂₋₆alkynyloxy, haloaryloxy,nitro, nitroC₁₋₆alkyl, nitroC₂₋₆alkenyl, nitroaryl, nitroheterocyclyl,azido, amino, C₁₋₆alkylamino, C₂₋₆alkenylamino, C₂₋₆alkynylamino,arylamino, heterocyclylamino acyl, C₁₋₆alkylacyl, C₂₋₆alkenylacyl,C₂₋₆alkynylacyl, arylacyl, heterocyclylacyl, acylamino, acyloxy,aldehydo, C₁₋₆alkylsulphonyl, arylsulphonyl, C₁₋₆alkylsulphonylamino,arylsulphonylamino, C₁₋₆alkylsulphonyloxy, arylsulphonyloxy,C₁₋₆alkylsulphenyl, C₂₋₆alklysulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, C₁₋₆alkylthio, arylthio, acylthio and cyano;each 5 or 6 membered heterocyclyl group may have 1, 2, 3 or 4heteroatoms selected from O, S and N and may be saturated, unsaturatedor aromatic; or a pharmaceutically acceptable salt, stereoisomer orgeometric isomer thereof.
 14. A compound of claim 13 which is:


15. A compound having the following formula:

in which R² is (CH₂)_(n)NR⁹R¹⁰; R⁵ is H or C₁₋₄ alkyl; R⁶ is H, halo,(CH₂)_(n) 5 or 6 membered heterocyclyl in which the heterocyclyl groupis optionally substituted or C₂₋₄ alkynyl; provided that one of R⁵ andR⁶ is not hydrogen; R⁸ is H, SO₂ aryl in which the aryl group isoptionally substituted, C₁₋₄ alkyl or (CH₂)_(n) aryl; R⁹ and R¹⁰ areindependently selected from H, C₁₋₈ alkyl optionally interrupted with O,CN, (CH₂)_(n) aryl in which the aryl group is optionally substituted andin which the aryl group is optionally fused with a 5 or 6 memberedheterocyclyl, (CH₂)_(n) C₃₋₈ cycloalkyl in which the cycloalkyl group isoptionally substituted, (CH₂)_(n) 5 or 6 membered heterocyclyl in whichthe heterocyclyl group is optionally substituted, SO₂ aryl in which thearyl group is optionally substituted and C₁₋₄ alkoxy; n is 1,2 or 3;wherein optional substituents are selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heterocyclyl, halo,haloC₁₋₆alkyl, CF₃, haloC₃₋₆cycloalkyl, haloC₂₋₆alkenyl,haloC₂₋₆alkynyl, haloaryl, haloheterocycylyl, hydroxy, C₁₋₆ alkoxy,OCF₃, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, aryloxy, heterocyclyloxy, carboxy,haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy, haloC₂₋₆alkynyloxy, haloaryloxy,nitro, nitroC₁₋₆alkyl, nitroC₂₋₆alkenyl, nitroaryl, nitroheterocyclyl,azido, amino, C₁₋₆alkylamino, C₂₋₆alkenylamino, C₂₋₆alkynylamino,arylamino, heterocyclylamino acyl, C₁₋₆alkylacyl, C₂₋₆alkenylacyl,C₂₋₆alkynylacyl, arylacyl, heterocyclylacyl, acylamino, acyloxy,aldehydo, C₁₋₆alkylsulphonyl, arylsulphonyl, C₁₋₆alkylsulphonylamino,arylsulphonylamino, C₁₋₆alkylsulphonyloxy, arylsulphonyloxy,C₁₋₆alkylsulphenyl, C₂₋₆alklysulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, C₁₋₆alkylthio, arylthio, acylthio and cyano;each 5 or 6 membered heterocyclyl group may have 1, 2, 3 or 4heteroatoms selected from O, S and N and may be saturated, unsaturatedor aromatic; or a pharmaceutically acceptable salt, stereoisomer orgeometric isomer thereof.